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  • A Feedback Circuitry between Polycomb Signaling and Fructose-1, 6-Bisphosphatase Enables Hepatic and Renal Tumorigenesis
    Cancer Res. (IF 8.378) Pub Date : 2020-01-22
    Kun Liao; Shuye Deng; Liyan Xu; Wenfeng Pan; Shiyu Yang; Fufu Zheng; Xingui Wu; Hongrong Hu; Zhijun Liu; Junhang Luo; Rui Zhang; Dong-Ming Kuang; Jiajun Dong; Yi Wu; Hui Zhang; Penghui Zhou; Jin-Xin Bei; Yang Xu; Yin Ji; Peng Wang; Huai-Qiang Ju; Rui-Hua Xu; Bo Li

    Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. Significance: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.

    更新日期:2020-01-23
  • The MEK5-ERK5 kinase axis controls lipid metabolism in small cell lung cancer
    Cancer Res. (IF 8.378) Pub Date : 2020-01-22
    Sandra Cristea; Garry L. Coles; Daniel Hornburg; Maya Gershkovitz; Julia Arand; Siqi Cao; Triparna Sen; Stuart Charles Williamson; Jun W Kim; Alexandros P Drainas; Andrew He; Laurent Le Cam; Lauren Averett Byers; Michael P Snyder; Kévin Contrepois; Julien Sage

    Small cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here we investigated the contribution of the MAP kinase module MEK5/ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacological inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC.

    更新日期:2020-01-23
  • A prospective analysis of circulating plasma metabolites associated with ovarian cancer risk
    Cancer Res. (IF 8.378) Pub Date : 2020-01-22
    Oana A Zeleznik; A. Heather Eliassen; Peter Kraft; Elizabeth M. Poole; Bernard A Rosner; Sarah Jeanfavre; Amy A. Deik; Kevin Bullock; Daniel S Hitchcock; Julian Avila-Pacheco; Clary B. Clish; Shelley S. Tworoger

    Ovarian cancer has few known risk factors, hampering identification of high-risk women. We assessed the association of pre-diagnostic plasma metabolites (N=420) with risk of epithelial ovarian cancer, including both borderline and invasive tumors. 252 cases and 252 matched controls from the Nurses' Health Studies were included. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) comparing the 90th-10th percentile in metabolite levels, using the permutation-based Westfall and Young approach to account for testing multiple correlated hypotheses. Weighted gene co-expression network analysis (WGCNA) modules (n=10 metabolite modules) and metabolite set enrichment analysis (MSEA; n=23 metabolite classes) were also evaluated. An increase in pseudouridine levels from the 10th to the 90th percentile was associated with a 2.5-fold increased risk of overall ovarian cancer (OR=2.56, 95%CI=1.48-4.45; p=0.001/adjusted-p=0.15); a similar risk estimate was observed for serous/poorly-differentiated tumors (n=176 cases; comparable OR=2.38, 95%CI=1.33-4.32, p=0.004/adjusted-p=0.55. For non-serous tumors (n=34 cases), pseudouridine and C36:2 phosphatidylcholine (PC) plasmalogen had the strongest statistical associations (comparable OR=9.84, 95%CI=2.89-37.82; p<0.001/adjusted-p=0.07; and OR=0.11, 95%CI=0.03-0.35; p<0.001/adjusted-p=0.06, respectively). Five WGCNA modules and 9 classes were associated with risk overall at FDR≤0.20. Triacylglycerols (TAGs) showed heterogeneity by tumor aggressiveness (case-only heterogeneity-p<0.0001). The TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. In summary, this study suggests that pseudouridine may be a novel risk factor for ovarian cancer and that TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features.

    更新日期:2020-01-23
  • Breast cancer cell-derived soluble CD44 promotes tumor progression by triggering macrophage IL-1β production
    Cancer Res. (IF 8.378) Pub Date : 2020-01-22
    Jeong-Hoon Jang; Do-Hee Kim; Jae Min Lim; Joon Won Lee; Su Jin Jeong; Kwang Pyo Kim; Young-Joon Surh

    Interleukin (IL)-1beta is a central regulator of systemic inflammatory response in breast cancer, but the precise regulatory mechanisms that dictate the overproduction of IL-1beta are largely unsolved. Here, we show that IL-1beta expression is increased by the co-culture of human monocyte-like cells and triple-negative breast cancer (TNBC) cells. In addition, macrophages robustly produced IL-1beta when exposed to the conditioned media of TNBC cells. Consistent with these observations, macrophage depletion decreased serum IL-1beta, and reduced breast cancer progression in an orthotopic breast cancer mouse model. Profiling the secretome of basal human breast cancer cells revealed that the CD44 antigen was the most differentially expressed protein in TNBC cells. Antibody-mediated neutralization of CD44 abrogated IL-1beta production in macrophages, and inhibited the growth of primary tumors. These results suggest IL-1beta-mediated oncogenic signaling is triggered by breast cancer cell membrane-derived soluble CD44 (sCD44), and that targeting sCD44 may provide an alternative therapeutic strategy for breast cancer treatment by modulating the inflammatory tumor microenvironment.

    更新日期:2020-01-23
  • Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness
    Cancer Res. (IF 8.378) Pub Date : 2020-01-21
    Vivek L. Patel; Evan L. Busch; Tara M. Friebel; Angel Cronin; Goska Leslie; Lesley McGuffog; Julian Adlard; Simona Agata; Bjarni A. Agnarsson; Munaza Ahmed; Kristiina Aittomäki; Elisa Alducci; Irene L. Andrulis; Adalgeir Arason; Norbert Arnold; Grazia Artioli; Brita Arver; Bernd Auber; Jacopo Azzollini; Judith Balmaña; Rosa B. Barkardottir; Daniel R. Barnes; Alicia Barroso; Daniel Barrowdale; Muriel Belotti; Javier Benitez; Brigitte Bertelsen; Marinus J. Blok; Istvan Bodrogi; Valérie Bonadona; Bernardo Bonanni; Davide Bondavalli; Susanne E. Boonen; Julika Borde; Ake Borg; Angela R. Bradbury; Angela Brady; Carole Brewer; Joan Brunet; Bruno Buecher; Saundra S. Buys; Santiago Cabezas-Camarero; Trinidad Caldés; Almuth Caliebe; Maria A. Caligo; Mariarosaria Calvello; Ian G. Campbell; Ileana Carnevali; Estela Carrasco; Tsun L. Chan; Annie T.W. Chu; Wendy K. Chung; Kathleen B.M. Claes; GEMO Study Collaborators; EMBRACE Collaborators; Jackie Cook; Laura Cortesi; Fergus J. Couch; Mary B. Daly; Giuseppe Damante; Esther Darder; Rosemarie Davidson; Miguel de la Hoya; Lara Della Puppa; Joe Dennis; Orland Díez; Yuan Chun Ding; Nina Ditsch; Susan M. Domchek; Alan Donaldson; Bernd Dworniczak; Douglas F. Easton; Diana M. Eccles; Rosalind A. Eeles; Hans Ehrencrona; Bent Ejlertsen; Christoph Engel; D. Gareth Evans; Laurence Faivre; Ulrike Faust; Lídia Feliubadaló; Lenka Foretova; Florentia Fostira; George Fountzilas; Debra Frost; Vanesa García-Barberán; Pilar Garre; Marion Gauthier-Villars; Lajos Géczi; Andrea Gehrig; Anne-Marie Gerdes; Paul Gesta; Giuseppe Giannini; Gord Glendon; Andrew K. Godwin; David E. Goldgar; Mark H. Greene; Angelica M. Gutierrez-Barrera; Eric Hahnen; Ute Hamann; Jan Hauke; Natalie Herold; Frans B.L. Hogervorst; Ellen Honisch; John L. Hopper; Peter J. Hulick; KConFab Investigators; HEBON Investigators; Louise Izatt; Agnes Jager; Paul James; Ramunas Janavicius; Uffe Birk Jensen; Thomas Dyrso Jensen; Oskar Th. Johannsson; Esther M. John; Vijai Joseph; Eunyoung Kang; Karin Kast; Johanna I. Kiiski; Sung-Won Kim; Zisun Kim; Kwang-Pil Ko; Irene Konstantopoulou; Gero Kramer; Lotte Krogh; Torben A. Kruse; Ava Kwong; Mirjam Larsen; Christine Lasset; Charlotte Lautrup; Conxi Lazaro; Jihyoun Lee; Jong Won Lee; Min Hyuk Lee; Johannes Lemke; Fabienne Lesueur; Annelie Liljegren; Annika Lindblom; Patricia Llovet; Adria Lopez-Fernández; Irene Lopez-Perolio; Victor Lorca; Jennifer T. Loud; Edmond S.K. Ma; Phuong L. Mai; Siranoush Manoukian; Veronique Mari; Lynn Martin; Laura Matricardi; Noura Mebirouk; Veronica Medici; Hanne E.J. Meijers-Heijboer; Alfons Meindl; Arjen R. Mensenkamp; Clare Miller; Denise Molina Gomes; Marco Montagna; Thea M. Mooij; Lidia Moserle; Emmanuelle Mouret-Fourme; Anna Marie Mulligan; Katherine L. Nathanson; Marie Navratilova; Heli Nevanlinna; Dieter Niederacher; Finn C. Cilius Nielsen; Liene Nikitina-Zake; Kenneth Offit; Edith Olah; Olufunmilayo I. Olopade; Kai-Ren Ong; Ana Osorio; Claus-Eric Ott; Domenico Palli; Sue K. Park; Michael T. Parsons; Inge Sokilde Pedersen; Bernard Peissel; Ana Peixoto; Pedro Pérez-Segura; Paolo Peterlongo; Annabeth Høgh Petersen; Mary E. Porteous; Miguel Angel Pujana; Paolo Radice; Juliane Ramser; Johanna Rantala; Muhammad U. Rashid; Kerstin Rhiem; Piera Rizzolo; Mark E. Robson; Matti A. Rookus; Caroline M. Rossing; Kathryn J. Ruddy; Catarina Santos; Claire Saule; Rosa Scarpitta; Rita K. Schmutzler; Hélène Schuster; Leigha Senter; Caroline M. Seynaeve; Payal D. Shah; Priyanka Sharma; Vivian Y. Shin; Valentina Silvestri; Jacques Simard; Christian F. Singer; Anne-Bine Skytte; Katie Snape; Angela R. Solano; Penny Soucy; Melissa C. Southey; Amanda B. Spurdle; Linda Steele; Doris Steinemann; Dominique Stoppa-Lyonnet; Agostina Stradella; Lone Sunde; Christian Sutter; Yen Y. Tan; Manuel R. Teixeira; Soo Hwang Teo; Mads Thomassen; Maria Grazia Tibiletti; Marc Tischkowitz; Silvia Tognazzo; Amanda E. Toland; Stefania Tommasi; Diana Torres; Angela Toss; Alison H. Trainer; Nadine Tung; Christi J. van Asperen; Frederieke H. van der Baan; Lizet E. van der Kolk; Rob B. van der Luijt; Liselotte P. van Hest; Liliana Varesco; Raymonda Varon-Mateeva; Alessandra Viel; Jeroen Vierstrate; Roberta Villa; Anna von Wachenfeldt; Philipp Wagner; Shan Wang-Gohrke; Barbara Wappenschmidt; Jeffrey N. Weitzel; Greet Wieme; Siddhartha Yadav; Drakoulis Yannoukakos; Sook-Yee Yoon; Cristina Zanzottera; Kristin K. Zorn; Anthony V. D'Amico; Matthew L. Freedman; Mark M. Pomerantz; Georgia Chenevix-Trench; Antonis C. Antoniou; Susan L. Neuhausen; Laura Ottini; Henriette Roed Nielsen; Timothy R. Rebbeck

    Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 ( BRCA1/2 ) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1 . These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

    更新日期:2020-01-22
  • SLC43A3 is a Biomarker of Sensitivity to the Telomeric DNA Damage Mediator 6-Thio-2'-Deoxyguanosine
    Cancer Res. (IF 8.378) Pub Date : 2020-01-16
    Ilgen Mender; Kimberly Batten; Michael Peyton; Aishwarya Vemula; Crystal Cornelius; Luc Girard; Boning Gao; John D. Minna; Jerry W Shay

    Cell membrane transporters facilitate the passage of nucleobases and nucleosides for nucleotide synthesis and metabolism, and are important for the delivery of nucleoside analogues used in anti-cancer drug therapy. Here, we investigated if cell membrane transporters are involved in the cellular uptake of the nucleoside analogue DNA damage mediator 6-thio-2'-deoxyguanosine (6-thio-dG). A large panel of non-small cell lung cancer (NSCLC) cell lines (73 of 77) were sensitive to 6-thio-dG; only 4 NSCLC lines were resistant to 6-thio-dG . When analyzed by microarray and RNA sequencing, the resistant NSCLC cell lines clustered together, providing a molecular signature for patients that may not respond to 6-thio-dG. Significant downregulation of solute carrier family 43 A3 (SLC43A3), an equilibrative nucleobase transporter, was identified as a candidate in this molecular resistance signature. High levels of SLC43A3 mRNA predicted sensitivity to 6-thio-dG and therefore SLC43A3 could serve as a promising biomarker for 6-thio-dG sensitivity in NSCLC patients.

    更新日期:2020-01-16
  • Linking transcriptomic and imaging data defines features of a favorable tumor immune microenvironment and identifies a combination biomarker for primary melanoma
    Cancer Res. (IF 8.378) Pub Date : 2020-01-16
    Robyn D. Gartrell-Corrado; Andrew X Chen; Emanuelle M. Rizk; Douglas K Marks; Margaret H Bogardus; Thomas D Hart; Andrew M Silverman; Claire-Audrey Y Bayan; Grace G Finkel; Luke W Barker; Kimberly M Komatsubara; Richard D. Carvajal; Basil A Horst; Rui Chang; Anthea Monod; Raul Rabadan; Yvonne M Saenger

    Patients with resected stage II-III melanoma have approximately a 35% chance of death from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an interferon-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTLs) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary to metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR- macrophages. The HLA-DR- subset co-expressed CD163+CSF1R+ at higher levels than CD68+HLA-DR+ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy.

    更新日期:2020-01-16
  • An ABC transporter drives medulloblastoma pathogenesis by regulating Sonic Hedgehog signaling
    Cancer Res. (IF 8.378) Pub Date : 2020-01-16
    Juwina Wijaya; BaoHan T Vo; Jingjing Liu; Beisi Xu; Gang Wu; Yao Wang; Junmin Peng; Jin Zhang; Laura J Janke; Brent A. Orr; Jiyang Yu; Martine F. Roussel; John D Schuetz

    Mutations in Sonic hedgehog (SHH) signaling promote aberrant proliferation and tumor growth. SHH medulloblastoma (MB) is among the most frequent brain tumors in children less than three years of age. While key components of the SHH pathway are well-known, we hypothesized that new disease-modifying targets of SHH MB might be identified from large-scale bioinformatics and systems biology analyses. Using a data-driven systems biology approach, we built a medulloblastoma-specific interactome. The ATP-binding cassette transporter ABCC4 was identified as a modulator of SHH-MB. Accordingly, increased ABCC4 expression correlated with poor overall survival in SHH MB patients. Knockdown of ABCC4 expression markedly blunted the constitutive activation of the SHH pathway secondary to Ptch1 or Sufu insufficiency. In human tumor cell lines, ABCC4 knockdown and inhibition reduced full-length GLI3 levels. In a clinically relevant murine SHH MB model, targeted ablation of Abcc4 in primary tumors significantly reduced tumor burden and extended the lifespan of tumor-bearing mice. These studies reveal ABCC4 as a potent SHH pathway regulator and a new candidate to target with the potential to improve SHH MB therapy.

    更新日期:2020-01-16
  • Towards multi-drug adaptive therapy
    Cancer Res. (IF 8.378) Pub Date : 2020-01-16
    Jeffrey West; Li You; Jingsong Zhang; Robert A Gatenby; Joel S Brown; Paul K. Newton; Alexander R.A. Anderson

    A new ecologically inspired paradigm in cancer treatment known as "adaptive therapy" capitalizes on competitive interactions between drug-sensitive and drug-resistant subclones. The goal of adaptive therapy is to maintain a controllable stable tumor burden by allowing a significant population of treatment sensitive cells to survive. These, in turn, suppress proliferation of the less fit resistant populations. However, there remain several open challenges in designing adaptive therapies, particularly in extending these therapeutic concepts to multiple treatments. We present a cancer treatment case study (metastatic castrate resistant prostate cancer) as a point of departure to illustrate three novel concepts to aid the design of multi-drug adaptive therapies. First, frequency-dependent "cycles" of tumor evolution can trap tumor evolution in a periodic, controllable loop. Second, the availability and selection of treatments may limit the evolutionary "absorbing region" reachable by the tumor. Third, the velocity of evolution significantly influences the optimal timing of drug sequences. These three conceptual advances provide a path forward for multi-drug adaptive therapy.

    更新日期:2020-01-16
  • Activation of canonical BMP4-SMAD7 signaling suppresses breast cancer metastasis
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Bedrich L. Eckhardt; Yuan Cao; Andrew D Redfern; Lap Hing Chi; Allan D Burrows; Suraya Roslan; Erica K. Sloan; Belinda S. Parker; Sherene Loi; Naoto T. Ueno; Peter K. H. Lau; Bruce Latham; Robin L Anderson

    Metastasis is the major cause of death in cancer patients; with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including SMAD7, via activation of canonical BMP-SMAD signaling. Restored BMP4 expression, or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitising cancer cells to anoikis, thereby reducing the number of circulating tumour cells. Gene silencing of BMP4, or its downstream mediator SMAD7, reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in breast cancer patients, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease.

    更新日期:2020-01-16
  • Increased Tumor Penetration of Single-Domain Antibody Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Ian Nessler; Eshita Khera; Steven Vance; Anna Kopp; Qifeng Qiu; Thomas A. Keating; Adnan O Abu-Yousif; Thomas Sandal; James Legg; Lorraine Thompson; Normann Goodwin; Greg M Thurber

    Targeted delivery of chemotherapeutics aims to increase efficacy and lower toxicity by concentrating drugs at the site-of-action, a method embodied by the seven current FDA approved antibody-drug conjugates (ADCs). However, a variety of pharmacokinetic challenges result in relatively narrow therapeutic windows for these agents, hampering the development of new drugs. Here, we use a series of Prostate-Specific Membrane Antigen (PSMA)-binding single-domain (Humabody®) ADC constructs to demonstrate that tissue penetration of protein-drug conjugates plays a major role in therapeutic efficacy. Counterintuitively, a construct with lower in vitro potency resulted in higher in vivo efficacy than other protein-drug conjugates. Biodistribution data, tumor histology images, spheroid experiments, in vivo single-cell measurements, and computational results demonstrate that a smaller size and slower internalization rate enabled higher tissue penetration and more cell killing. The results also illustrate the benefits of linking an albumin binding domain to the single-domain ADCs. A construct lacking an albumin binding domain was rapidly cleared leading to lower tumor uptake (%ID/g) and decreased in vivo efficacy. In conclusion, these results provide evidence that reaching the maximum number of cells with a lethal payload dose correlates more strongly with in vivo efficacy than total tumor uptake or in vitro potency alone for these protein-drug conjugates. Computational modeling and protein engineering can be used to custom design an optimal framework for controlling internalization, clearance, and tissue penetration to maximize cell killing.

    更新日期:2020-01-15
  • Highlights from Recent Cancer Literature
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    American Association for Cancer Research

    ![][1] Cells representing a BRCAness phenotype are vulnerable to PARP inhibitors and DNA damaging agents. However, most tumors do not demonstrate a BRCAness phenotype. Although recent studies reveal that BRCAness may be induced through inhibition of CDK12, small-molecule CDK12

    更新日期:2020-01-15
  • Statins Limit Coenzyme Q Synthesis and Metabolically Synergize with MEK Inhibition in Pancreatic Tumors
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Thekla Cordes; Christian M. Metallo

    Tumors frequently increase expression of enzymes in the mevalonate biosynthesis pathway. Statins inhibit flux through this pathway, but if and how such treatments elicit a therapeutic benefit in cancer remains unclear. In this issue of Cancer Research , McGregor and colleagues perform in vivo metabolic tracing to demonstrate that mouse pancreatic ductal adenocarcinoma (PDAC) tumors and human PDAC cell lines require this pathway for coenzyme Q (CoQ) synthesis and redox homeostasis. Simvastatin treatment reduces CoQ synthesis and promotes oxidative stress and apoptosis in tumors when administered in combination with a MEK inhibitor, providing a new mechanism through which statin treatment may impact PDAC growth. See related article by McGregor et al., [p. 175][1] [1]: /lookup/volpage/80/175?iss=2

    更新日期:2020-01-15
  • EMT and Back Again: Visualizing the Dynamic Phenotypes of Metastasis
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Fred Bunz

    To what extent does the acquisition of mesenchymal phenotypes by tumor epithelial cells contribute to metastasis? A definitive answer to this question has remained elusive despite much experimentation and debate. Recently, an influential study based on fluorescence-based lineage tracing technology provided evidence that very few of the cells that populate experimental metastases in fact undergo the epithelial-to-mesenchymal transition. Persistent questions regarding the concordance between marker conversion and cell phenotypes prompted Lourenco and colleagues to complement their lineage tracking system with single-cell analysis. This granular approach provides an unprecedented view of the phenotypic transitions that take place during metastasis and their striking heterogeneity. See related article by Lourenco et al., [p. 163][1] [1]: /lookup/volpage/80/163?iss=2

    更新日期:2020-01-15
  • Correction: Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Dongpo Cai; Vaughan M. Latham; Xinxin Zhang; Geoffrey I. Shapiro

    In the original version of [this article][1] ([1][2]), the incorrect sequence for the oligonucleotide containing XIAP was reported. The error has been corrected in the latest online PDF version of the article. The authors regret this error. 1. 1.[↵][3]1. Cai D, 2. Latham VM Jr., 3.

    更新日期:2020-01-15
  • Correction: Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4–NDRG1 Axis
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Nandini Verma; Anna-Katharina Müller; Charu Kothari; Effrosini Panayotopoulou; Amir Kedan; Michael Selitrennik; Gordon B. Mills; Lan K. Nguyen; Sungyoung Shin; Thomas Karn; Uwe Holtrich; Sima Lev

    In the original version of [this article][1] ([1][2]), two instances of inadvertent duplication of crystal violet staining images occurred in Fig. 1D (control shRNA conditions in MDA-MB-468 and BT-20) and in Fig. 1F (0 μmol/L gefitinib control conditions in MDA-468 and BT-20). In addition, the same

    更新日期:2020-01-15
  • Editor's Note: Dominant-Negative Fas Mutation Is Reversed by Down-expression of c-FLIP
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Marie Bénéteau; Sophie Daburon; Jean-François Moreau; Jean-Luc Taupin; Patrick Legembre

    The editors are publishing this note to alert readers to concerns about [this article][1] ([1][2]). The same Western blot analysis image was used for Jurkat-R cells in Fig. 4A and for Jurkat parental cells in Fig. 1B of another article previously published by the authors ([2][3]). In addition, lane

    更新日期:2020-01-15
  • Editor's Note: p38 Mitogen-activated Protein Kinase Pathway Suppresses Cell Survival by Inducing Dephosphorylation of Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase1,2
    Cancer Res. (IF 8.378) Pub Date : 2020-01-15
    Song-Ping Li; Melissa R. Junttila; Jiahuai Han; Veli-Matti Kähäri; Jukka Westermarck

    The editors are publishing this note to alert readers to concerns about [this article][1] ([1][2]). There is evidence of inconsistent splicing in several Western blot images. Specifically, in Fig. 1C, splicing is evident between the first and second lanes of all proteins except p-JNK. Likewise, in

    更新日期:2020-01-15
  • Metabolic Reprogramming in Cancer is Induced to Increase Proton Production
    Cancer Res. (IF 8.378) Pub Date : 2020-01-13
    Huiyan Sun; Yi Zhou; Michael Francis Skaro; Yiran Wu; Zexing Qu; Fenglou Mao; Suwen Zhao; Ying Xu

    Considerable metabolic reprogramming has been observed in a conserved manner across multiple cancer types, but their true causes remain elusive. We present an analysis of around 50 such reprogrammed metabolisms (RMs) including the Warburg effect, nucleotide de novo synthesis and sialic acid biosynthesis in cancer. Analyses of the biochemical reactions conducted by these RMs, coupled with gene expression data of their catalyzing enzymes, in 7,011 tissues of 14 cancer types, revealed that all RMs produce more H+ than their original metabolisms. These data strongly support a model that these RMs are induced or selected to neutralize a persistent intracellular alkaline stress due to chronic inflammation and local iron overload. To sustain these RMs for survival, cells must find metabolic exits for the non-proton products of these RMs in a continuous manner, some of which pose major challenges, such as nucleotides and sialic acids, since they are electrically charged. This analysis strongly suggests that continuous cell division and other cancerous behaviors are ways for the affected cells to remove such products in a timely and sustained manner. As supporting evidence, this model can offer simple and natural explanations to a range of long-standing open questions in cancer research including the cause of the Warburg effect.

    更新日期:2020-01-14
  • The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles: an analysis from the Ovarian Cancer Cohort Consortium (OC3)
    Cancer Res. (IF 8.378) Pub Date : 2020-01-13
    Britton Trabert; Shelley S. Tworoger; Katie M. O'Brien; Mary K. Townsend; Renée T Fortner; Edwin S. Iversen; Patricia Hartge; Emily White; Pilar Amiano; Alan A Arslan; Leslie Bernstein; Louise A. Brinton; Julie E. Buring; Laure Dossus; Gary E. Fraser; Mia M. Gaudet; Graham G. Giles; Inger T. Gram; Holly R Harris; Judith Hoffman Bolton; Annika Idahl; Michael E. Jones; Rudolf Kaaks; Victoria A. Kirsh; Synnove F. Knutsen; Marina Kvaskoff; James V. Lacey; I-Min Lee; Roger L. Milne; N. Charlotte Onland-Moret; Kim Overvad; Alpa V. Patel; Ulrike Peters; Jenny N Poynter; Elio Riboli; Kim Robien; Thomas E. Rohan; Dale P. Sandler; Catherine Schairer; Leo J. Schouten; Veronica Wendy Setiawan; Anthony J. Swerdlow; Ruth C. Travis; Antonia Trichopoulou; Piet A. van den Brandt; Kala Visvanathan; Lynne R. Wilkens; Alicja Wolk; Anne Zeleniuch-Jacquotte; Nicolas Wentzensen

    Repeated exposure to the acute pro-inflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted hazard ratios (HR) between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per five-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity=0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity=0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from ~300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk which cumulates through life, suggesting this as an important area for identifying intervention strategies.

    更新日期:2020-01-14
  • Lymphoma angiogenesis is orchestrated by noncanonical signaling pathways
    Cancer Res. (IF 8.378) Pub Date : 2020-01-13
    Marleen Gloger; Lutz Menzel; Michael Grau; Anne-Clemence Vion; Ioannis Anagnostopoulos; Myroslav Zapukhlyak; Kerstin Gerlach; Thomas Kammertöns; Thomas Hehlgans; Maria Zschummel; Georg Lenz; Holger Gerhardt; Uta E. Höpken; Armin Rehm

    Tumor-induced remodeling of the microenvironment relies on the formation of blood vessels, which go beyond the regulation of metabolism, shaping a maladapted survival niche for tumor cells. In high-grade B-cell lymphoma, angiogenesis correlates with poor prognosis, but attempts to target established pro-angiogenic pathways within the vascular niche have been inefficient. Here, we analyzed Myc-driven B-cell lymphoma-induced angiogenesis in mice. A few lymphoma cells were sufficient to activate the angiogenic switch in lymph nodes. A unique morphology of dense microvessels emerged without obvious tip cell guidance and reliant on blood endothelial cell (BEC) proliferation. The transcriptional response of BECs was inflammation-independent. Conventional HIF-1α or Notch signaling routes prevalent in solid tumors were not activated. Instead, a nonconventional hypersprouting morphology was orchestrated by lymphoma-provided vascular endothelial growth factor (VEGF)-C and lymphotoxin (LT). Interference with VEGF receptor-3 and LTβ receptor signaling pathways abrogated lymphoma angiogenesis, thus revealing targets to block lymphomagenesis.

    更新日期:2020-01-14
  • Therapy-induced senescence drives bone loss
    Cancer Res. (IF 8.378) Pub Date : 2020-01-13
    Sheila A Stewart; Zhangting Yao; Bhavna Murali; Qihao Ren; Xianmin Luo; Douglas V Faget; Tom Cole; Biancamaria Ricci; Dinesh Thotala; Joseph Monahan; Jan M van Deursen; Darren Baker; Roberta Faccio; Julie K Schwarz

    Chemotherapy is important for cancer treatment; however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life.

    更新日期:2020-01-14
  • Host Wnt5a Potentiates Microenvironmental Regulation of Ovarian Cancer Metastasis
    Cancer Res. (IF 8.378) Pub Date : 2020-01-13
    Marwa Asem; Allison M. Young; Carlysa Oyama; Alejandro G Claure De La Zerda; Yueying Liu; Jing Yang; Tyvette S. Hilliard; Jeffery Johnson; Elizabeth I. Harper; Ian Guldner; Siyuan Zhang; Toni M Page-Mayberry; William J. Kaliney; M. Sharon Stack

    The non-canonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden. Tumors formed in WNT5A knockout mice had elevated cytotoxic T cells, increased M1 macrophages and decreased M2 macrophages, indicating that host Wnt5a promotes an immunosuppressive microenvironment. The Src family kinase Fgr was identified as a downstream effector of Wnt5a. These results highlight a previously unreported role for host-expressed Wnt5a in ovarian cancer metastatis, and suggest Fgr as a novel target for inhibition of ovarian cancer metastatic progression.

    更新日期:2020-01-14
  • miR-149 suppresses breast cancer metastasis by blocking paracrine interactions with macrophages
    Cancer Res. (IF 8.378) Pub Date : 2020-01-10
    Ismael Sánchez-González; Anja Bobien; Christian Molnar; Simone Schmid; Michaela Strotbek; Melanie Boerries; Hauke Busch; Monilola A Olayioye

    Paracrine activation of cells contained in the tumor microenvironment promotes tumor progression and metastasis. In breast cancer, malignant cells recruit and educate macrophages into a M2 tumor-promoting phenotype that supports the metastatic spread of cancer cells. Here, we show that miR-149 functions as a metastasis-suppressing microRNA in breast cancer cells by limiting colony-stimulating factor-1 (CSF1)-dependent recruitment and M2 polarization of macrophages. In lymph node-positive, triple-negative breast cancer (TNBC) tissues, low miR-149 expression correlated with reduced macrophage infiltration and patient survival. By directly targeting CSF1, miR-149 expression in TNBC cell lines (MDA-MB-231 and BT-549) inhibited the recruitment of human monocytic THP-1 cells and primary human macrophages. Furthermore, in macrophages co-cultured with MDA-MB-231 cells expressing miR-149, epidermal growth factor (EGF) and amphiregulin expression levels were strongly reduced, resulting in reduced EGF receptor activation in the cancer cells. In vivo, lung metastases developing from orthotopic MDA-MB-231 tumors were reduced by 75% by miR-149 expression and this was associated with impaired M2 macrophage infiltration of the primary tumors. These data suggest that miR-149 downregulation functionally contributes to breast tumor progression by recruiting macrophages to the tumor and facilitating CSF1 and EGF receptor crosstalk between cancer cells and macrophages.

    更新日期:2020-01-10
  • Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers
    Cancer Res. (IF 8.378) Pub Date : 2020-01-10
    Suman Mukhopadhyay; Debanjan Goswami; Pavan P. Adiseshaiah; William Burgan; Ming Yi; Theresa M. Guerin; Serguei V. Kozlov; Dwight V Nissley; Frank McCormick

    Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for pancreatic cancer patients and contributes to a high rate of recurrence. Here we showed that oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. NRF2 contributed to chemoresistance and was associated with a poor prognosis in pancreatic cancer patients. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. Additionally, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for pancreatic cancer patients harboring KRAS mutation.

    更新日期:2020-01-10
  • BACH1 promotes pancreatic cancer metastasis by repressing epithelial genes and enhancing epithelial-mesenchymal transition
    Cancer Res. (IF 8.378) Pub Date : 2020-01-09
    Masaki Sato; Mitsuyo Matsumoto; Yuriko Saiki; Mahabub Alam; Hironari Nishizawa; Masahiro Rokugo; Andrey Brydun; Shinji Yamada; Mika K Kaneko; Ryo Funayama; Mamoru Ito; Yukinari Kato; Keiko Nakayama; Michiaki Unno; Kazuhiko Igarashi

    Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the poorest prognoses due to its highly malignant features. BTB and CNC homology 1 (BACH1) has been implicated in RAS-driven tumor formation. We focused on the role of BACH1 in PDAC, more than 90% of which have KRAS mutation. Knockdown of BACH1 in PDAC cell lines reduced cell migration and invasion in part by increasing E-cadherin expression, whereas its overexpression showed opposite effects. BACH1 directly repressed the expression of FOXA1 which is known to activate the expression of CDH1 encoding E-cadherin and to inhibit epithelial-mesenchymal transition. BACH1 also directly repressed the expression of genes important for epithelial cell adhesion including CLDN3 and CLDN4. In a mouse orthotopic implantation model, BACH1 was required for the high metastatic ability of AsPC-1 cells. Immunohistochemistry analysis of clinical specimens with a newly developed anti-BACH1 monoclonal antibody revealed that high expression of BACH1 is a poor prognostic factor. These results suggest that the gene regulatory network of BACH1 and downstream genes including CDH1 contribute to the malignant features of PDAC by regulating epithelial-mesenchymal transition.

    更新日期:2020-01-10
  • The immunosuppressive microenvironment in BRCA1-IRIS-overexpressing TNBC tumors is induced by bidirectional interaction with tumor-associated macrophages
    Cancer Res. (IF 8.378) Pub Date : 2020-01-09
    Eman Sami; Bibbin T Paul; James A Koziol; Wael M. ElShamy

    Tumor-associated macrophages (TAMs) promote triple-negative breast cancer (TNBC) progression. Here, we report BRCA1-IRIS overexpressing (IRISOE) TNBC cells secrete high levels of GM-CSF in a HIF-1a- and a NF-kB-dependent manner to recruit macrophages to IRISOE cells and polarize them to pro-tumor M2 TAMs. GM-CSF triggered TGF-b1 expression by M2 TAMs by activating STAT5, NF-kB and/or ERK signaling. Despite expressing high levels of TGF-b1 receptors on their surface, IRISOE TNBC cells channeled TGF-b1/TbRI/II signaling towards AKT, not SMAD, which activated stemness/EMT-phenotypes. In orthotopic and syngeneic mouse models, silencing or inactivating IRIS in TNBC cells lowered the levels of circulating GM-CSF, suppressed TAM recruitment, and decreased the levels of circulating TGF-b1. Co-injecting macrophages with IRISOE TNBC cells induced earlier metastasis in athymic mice accompanied by high levels of circulating GM-CSF and TGF-b1. IRISOE TNBC cells expressed low levels of calreticulin (the "eat me" signal for macrophages) and high levels CD47 (the "don't eat me" signal for macrophages) and PD-L1 (a T-cell inactivator) on their surface. Accordingly, IRISOE TNBC tumors had significantly few CD8+/PD-1+ cytotoxic T-cells and more CD25+/FOXP3+-regulatory T cells. These data show that the bi-directional interaction between IRISOE cells and macrophages triggers an immunosuppressive microenvironment within TNBC tumors that is favorable for the generation of immune-evading/stem-like/IRISOE TNBC metastatic precursors. Inhibiting this interaction may inhibit disease progression and enhance patients' overall survival

    更新日期:2020-01-10
  • Argonautes in Extracellular Vesicles: Artifact or Selected Cargo?
    Cancer Res. (IF 8.378) Pub Date : 2020-01-09
    Alissa M. Weaver; James G. Patton

    Argonaute-2 (Ago2) is a key component of the RNA-induced silencing complex that mediates downregulation of mRNA by miRNAs. Its presence in extracellular vesicles (EV) has been postulated to be important for the activity of EV-carried miRNA in modulating gene expression in recipient cells. However, whether it is in fact contained within EVs or is instead an extravesicular contaminant is controversial. In this opinion piece, we argue that the ability to detect Ago2 in EVs is a result of multiple factors, including cell source, cell signaling control of Ago2 trafficking to EVs, experimental conditions, and detection methods.

    更新日期:2020-01-09
  • Genome-Wide CRISPR-Cas9 Screen Reveals Selective Vulnerability of ATRX-Mutant Cancers to WEE1 Inhibition
    Cancer Res. (IF 8.378) Pub Date : 2020-01-09
    Junbo Liang; Hong Zhao; Bill H. Diplas; Song Liu; Jianmei Liu; Dingding Wang; Yan Lu; Qing Zhu; Jiayu Wu; Wenjia Wang; Hai Yan; Yi-Xin Zeng; Xiaoyue Wang; Yuchen Jiao

    The tumor suppressor gene ATRX is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX -mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1 , uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro , as well as xenografts in vivo . The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage–induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX . Significance: ATRX -mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in ATRX -deficient cancers.

    更新日期:2020-01-09
  • Tumor Cell-Derived IL-1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer
    Cancer Res. (IF 8.378) Pub Date : 2020-01-08
    Shipra Das; Beny Shapiro; Emily A Vucic; Sandra Vogt; Dafna Bar-Sagi

    Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell-derived pro-inflammatory cytokine, interleukin-1β (IL-1β) is essential for the establishment of the pro-tumorigenic PDA microenvironment. Tumor cell-derived IL-1β promoted the activation and secretory phenotype of quiescent pancreatic stellate cells (PSC) and established an immunosuppressive milieu mediated by M2 macrophages, MDSCs, CD1dhiCD5+ regulatory B cells and Th17 cells. Loss of tumor cell-derived IL-1 signaling in tumor stroma enabled intra-tumoral infiltration and activation of CD8+ cytotoxic T cells, attenuated growth of pancreatic neoplasia and conferred survival advantage to PDA bearing mice. Accordingly, antibody-mediated neutralization of IL-1β significantly enhanced the anti-tumor activity of α-PD-1, and was accompanied by increased tumor infiltration of CD8+ T cells. Tumor cell expression of IL-1β in vivo was driven by microbial-dependent activation of toll-like receptor 4 (TLR4) signaling and subsequent engagement of the NLRP3 inflammasome. Collectively, these findings identify a hitherto unappreciated role for tumor cell-derived IL-1β in orchestrating an immune modulatory program that supports pancreatic tumorigenesis.

    更新日期:2020-01-08
  • Computational staining of pathology images to study the tumor microenvironment in lung cancer
    Cancer Res. (IF 8.378) Pub Date : 2020-01-08
    Shidan Wang; Ruichen Rong; Donghan M Yang; Junya Fujimoto; Shirley Yan; Ling Cai; Lin Yang; Danni Luo; Carmen Behrens; Edwin R. Parra; Bo Yao; Lin Xu; Tao Wang; Xiaowei Zhan; Ignacio I. Wistuba; John Minna; Yang Xie; Guanghua Xiao

    The spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). In order to facilitate the study of cellular spatial organization and interactions, we developed Histology-based Digital (HD)-Staining, a deep learning-based computation model, to segment the nuclei of tumor, stroma, lymphocyte, macrophage, karyorrhexis and red blood cells from standard Hematoxylin and Eosin (H&E)-stained pathology images in lung adenocarcinoma (ADC). Using this tool, we identified and classified cell nuclei and extracted 48 cell spatial organization-related features that characterize the TME. Using these features, we developed a prognostic model from the National Lung Screening Trial dataset, and independently validated the model in The Cancer Genome Atlas (TCGA) lung ADC dataset, in which the predicted high-risk group showed significantly worse survival than the low-risk group (pv=0.001), with a hazard ratio of 2.23 [1.37-3.65] after adjusting for clinical variables. Furthermore, the image-derived TME features significantly correlated with the gene expression of biological pathways. For example, transcriptional activation of both the T-cell receptor (TCR) and programmed cell death protein 1 (PD1) pathways positively correlated with the density of detected lymphocytes in tumor tissues, while expression of the extracellular matrix organization pathway positively correlated with the density of stromal cells. In summary, we demonstrate that the spatial organization of different cell types is predictive of patient survival and associated with the gene expression of biological pathways.

    更新日期:2020-01-08
  • In situ DESI - MSI lipidomic profiles of breast cancer molecular subtypes and precursor lesions.
    Cancer Res. (IF 8.378) Pub Date : 2020-01-07
    Adriana Leandra Santoro; Rodrigo D Drummond; Israel Tojal da Silva; Severino Silva Ferreira; Luiz Juliano; Pedro Henrique Vendramini; Monique Batista da Costa Lemos; Marcos N Eberlin; Victor Piana de Andrade

    Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pre-treatment in frozen samples. Here we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest (ROI) were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200μm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [(taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC form ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared to Luminal A and HER-2 subtypes. DCIS and IBC were distinguished based on cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE(P-16:0/22:6, m/z 746.5099, and PS(38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer with potential implications for breast cancer pathogenesis.

    更新日期:2020-01-07
  • Inhibiting translation elongation with SVC112 suppresses cancer stem cells and inhibits growth in head and neck squamous carcinoma
    Cancer Res. (IF 8.378) Pub Date : 2020-01-07
    Stephen B Keysar; Nathan Gomes; Bettina Miller; Brian C Jackson; Phuong N. Le; J. Jason Morton; Julie Reisinger; Tugs-Saikhan Chimed; Karina E. Gomez; Cera Nieto; Barbara Frederick; Gijsbertus J Pronk; Hilary L. Somerset; Aik-Choon Tan; Xiao-Jing Wang; David Raben; Tin Tin Su; Antonio Jimeno

    Cancer stem cells (CSCs) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater anti-proliferative effects on HNSCC cells compared to the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared to patient-matched cancer associated fibroblasts, while HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDXs), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response, and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs.

    更新日期:2020-01-07
  • A Bis-Indole-Derived NR4A1 Antagonist Induces PD-L1 Degradation and Enhances Anti-Tumor Immunity
    Cancer Res. (IF 8.378) Pub Date : 2020-01-07
    Keshav Karki; Gus A Wright; Kumaravel Mohankumar; Un-Ho Jin; Xing-Han Zhang; Stephen Safe

    PD-L1 is expressed in tumor cells and its interaction with PD-1 plays an important role in evading immune surveillance; this can be overcome using PD-L1 or PD-1 immunotherapy antibodies. This study reports a novel approach for targeting PD-L1. In human breast cancer cell lines and 4T1 mouse mammary tumor cells PD-L1 expression was regulated by the nuclear receptor NR4A1/Sp1 complex bound to the proximal GC-rich region of the PD-L1 gene promoter. Treatment of breast cancer cells with bis-indole-derived NR4A1 antagonists including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (Cl-OCH3) decreased expression of PD-L1 mRNA, promoter-dependent luciferase activity and protein. In in vivo studies using a syngeneic mouse model bearing orthotopically injected 4T1 cells Cl-OCH3 decreased tumor growth and weight and inhibited lung metastasis. Cl-OCH3 also decreased expression of CD3+/CD4+/CD25+/FoxP3+ regulatory T cells and increased the Teff/Treg ratio. Therefore, the potent anti-cancer activities of NR4A1 antagonists are also accompanied by enhanced anti-tumor immunity in PD-L1-expressing triple-negative breast cancer and thus represent a novel class of drugs that mimic immunotherapy.

    更新日期:2020-01-07
  • Runx2 deficiency in osteoblasts promotes myeloma progression by altering the bone microenvironment at new bone sites
    Cancer Res. (IF 8.378) Pub Date : 2020-01-07
    Xiaoxuan Xu; Chao Zhang; Timothy N. Trotter; Pramod S. Gowda; Yun Lu; Selvarangan Ponnazhagan; Amjad Javed; Juan Li; Yang Yang

    Multiple myeloma (MM) is a plasma cell malignancy that thrives in the bone marrow (BM), with frequent progression to new local and distant bone sites. Our previous studies demonstrated that MM cells at primary sites secrete soluble factors and suppress osteoblastogenesis via the inhibition of Runt-related transcription factor 2 (Runx2) in pre- and immature osteoblasts (OBs) in new bone sites, prior to the arrival of metastatic tumor cells. However, it is unknown whether OB-Runx2 suppression in new bone sites feeds back to promote MM dissemination to and progression in these areas. Hence, we developed a syngeneic mouse model of MM in which Runx2 is specifically deleted in the immature OBs of C57BL6/KaLwRij mice (OB-Runx2-/- mice) to study the effect of OB-Runx2 deficiency on MM progression in new bone sites. In vivo studies with this model demonstrated that OB-Runx2 deficiency attracts MM cells and promotes MM tumor growth in bone. Mechanistic studies further revealed that OB-Runx2 deficiency induces an immunosuppressive microenvironment in BM that is marked by an increase in the concentration and activation of myeloid-derived suppressor cells (MDSCs) and the suppression and exhaustion of cytotoxic CD8+ T cells. In contrast, MDSC depletion by either gemcitabine or 5-fluorouracil treatment in OB-Runx2-/- mice prevented these effects and inhibited MM tumor growth in BM. These novel discoveries demonstrate that OB-Runx2 deficiency in new bone sites promotes MM dissemination and progression by increasing metastatic cytokines and MDSCs in BM and inhibiting BM immunity. Importantly, MDSC depletion can block MM progression promoted by OB-Runx2 deficiency.

    更新日期:2020-01-07
  • Nudix hydrolase NUDT16 regulates 53BP1 protein by reversing 53BP1 ADP-ribosylation
    Cancer Res. (IF 8.378) Pub Date : 2020-01-07
    Fan Zhang; Lihong Lou; Bo Peng; Xiaotian Song; Ofer Reizes; Alexandru Almasan; Zihua Gong

    53BP1 controls two downstream sub-pathways, one mediated by PTIP and Artemis and the other by RIF1 and MAD2L2/Shieldin, to coordinate DNA repair pathway choices. However, the upstream regulator(s) of 53BP1 function in DNA repair remain unknown. We and others recently reported that TIRR associates with 53BP1 to stabilize it and prevents 53BP1 localization to DNA damage sites by blocking 53BP1 Tudor domain binding to H4K20me2 sites. Here, we report that the Nudix hydrolase NUDT16, a TIRR homolog, regulates 53BP1 stability. We identified a novel post-translational modification of 53BP1 by ADP-ribosylation that is targeted by a PAR-binding E3 ubiquitin ligase, RNF146, leading to 53BP1 polyubiquitination and degradation. In response to DNA damage, ADP-ribosylated 53BP1 increased significantly, resulting in its ubiquitination and degradation. These data suggest that NUDT16 plays a major role in controlling 53BP1 levels under both normal growth conditions and during DNA damage. Notably, overexpression of a NUDT16 catalytically inactive mutant blocked 53BP1 localization to double-strand breaks because: 1) the mutant binding to TIRR increased after IR; 2) the mutant enhanced 53BP1 Tudor domain binding to TIRR, and 3) the mutant impaired the interaction of 53BP1 Tudor domain with H4K20me2. Moreover, NUDT16's catalytic hydrolase activity was required for 53BP1 de-ADP-ribosylation, 53BP1 protein stability, and its function in cell survival. In summary, we demonstrate that NUDT16 regulates 53BP1 stability and 53BP1 recruitment at double-strand breaks, providing yet another mechanism of 53BP1 regulation.

    更新日期:2020-01-07
  • Combined MEK and PI3K/p110b inhibition as a novel targeted therapy for malignant mesothelioma displaying sarcomatoid features
    Cancer Res. (IF 8.378) Pub Date : 2020-01-07
    Miriam Marqués; Robin Tranchant; Blanca Risa-Ebrí; María L Suárez-Solís; Luis C Fernández; Enrique Carrillo-de-Santa-Pau; Natalia del Pozo; Jaime Martínez de Villarreal; Clément Meiller; Yves Allory; Yuna Blum; Christine Pirker; Balazs Hegedus; Simon T. Barry; Amancio Carnero; Walter Berger; Didier Jean; Francisco X Real

    Among malignant mesotheliomas (MM) the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to non-epithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2 coupled receptor subunit activated MEK/ERK and PI3K resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using Selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating non-epithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of Selumetinib and AZD8186 in MM patients with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of MM patients, for whom therapeutic options are currently lacking.

    更新日期:2020-01-07
  • Long noncoding RNA DRAIC inhibits prostate cancer progression by interacting with IKK to inhibit NF-κB activation
    Cancer Res. (IF 8.378) Pub Date : 2020-01-03
    Shekhar Saha; Manjari Kiran; Canan Kuscu; Ajay Chatrath; David Wotton; Marty W Mayo; Anindya Dutta

    DRAIC is a 1.7 kb spliced long noncoding RNA downregulated in castration-resistant advanced prostate cancer. Decreased DRAIC expression predicts poor patient outcome in prostate and seven other cancers, while increased DRAIC represses growth of xenografted tumors. Here we show that cancers with decreased DRAIC expression have increased NF-κB target gene expression. DRAIC downregulation increased cell invasion and soft agar colony formation; this was dependent on NF-κB activation. DRAIC interacted with subunits of the IκB kinase (IKK) complex to inhibit their interaction with each other, the phosphorylation of IκBα and the activation of NF-κB. These functions of DRAIC mapped to the same fragment containing bases 701-905. Thus, DRAIC lncRNA inhibits prostate cancer progression through suppression of NF-κB activation by interfering with IKK activity.

    更新日期:2020-01-04
  • EPIGENETIC TARGETING OF TERT-ASSOCIATED GENE EXPRESSION SIGNATURE IN HUMAN NEUROBLASTOMA WITH TERT OVEREXPRESSION
    Cancer Res. (IF 8.378) Pub Date : 2020-01-03
    Min Huang; Jasmine Zeki; Nathan Sumarsono; Garry L. Coles; Jordan S Taylor; Enrico Danzer; Matias Bruzoni; Florette K Hazard; Norman J Lacayo; Kathleen M Sakamoto; James C.Y. Dunn; Sheri L. Spunt; Bill Chiu

    Neuroblastoma is a deadly pediatric solid tumor with infrequent recurrent somatic mutations. Particularly, the pathophysiology of tumors without MYCN amplification remains poorly defined. Utilizing an unbiased approach, we performed gene set enrichment analysis of RNA-seq data from 498 neuroblastoma patients and revealed a differentially overexpressed gene signature in MYCN non-amplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpression and coordinated activation of oncogenic signaling pathways, including E2Fs, Wnt, Myc, and the DNA repair pathway. Promoter rearrangement of the TERT gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis in neuroblastoma, but TERT-associated oncogenic signaling remains unclear. ChIP-seq analysis of the human CLB-GA neuroblastoma cells harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. Brd4 and cyclin-dependent kinases (CDKs) had critical regulatory roles in the expression and chromatin activation of TERT and multiple TERT-associated genes. Epigenetically targeting Brd4 or CDKs with their respective inhibitors suppressed the expression of TERT and multiple TERT-associated genes in neuroblastoma with TERT overexpression or MYCN amplification. ChIP-seq and ChIP-qPCR provided evidence that the CDK inhibitor directly inhibited Brd4 recruitment to activate chromatin globally. Therefore, inhibiting Brd4 and CDK concurrently with AZD5153 and dinaciclib would be most effective in tumor growth suppression, which we demonstrated in neuroblastoma cell lines, primary human cells, and xenografts. In summary, we describe a unique mechanism in neuroblastoma with TERT overexpression and an epigenetically targeted novel therapeutic strategy.

    更新日期:2020-01-04
  • HIF-2-induced long non-coding RNA RAB11B-AS1 promotes hypoxia-mediated angiogenesis and breast cancer metastasis
    Cancer Res. (IF 8.378) Pub Date : 2020-01-03
    Yanling Niu; Lei Bao; Yan Chen; Chenliang Wang; Maowu Luo; Bo Zhang; Mi Zhou; Jennifer E. Wang; Yisheng V. Fang; Ashwani Kumar; Chao Xing; Yingfei Wang; Weibo Luo

    Hypoxia induces a vast array of long non-coding RNAs (lncRNAs) in breast cancer cells, but their biological functions remain largely unknown. Here we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF-2), but not HIF-1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells in vitro. Gain- and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion in vitro and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis.

    更新日期:2020-01-04
  • Epigenetic SMAD3 Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma
    Cancer Res. (IF 8.378) Pub Date : 2020-01-03
    Rafael Ikemori; Marta Gabasa; Paula Duch; Miguel Vizoso; Paloma Bragado; Marselina Arshakyan; Iuliana-Cristiana Luis; Albert Marín; Sebastian Morán; Manuel Castro; Gemma Fuster; Sabrina Gea-Sorli; Toni Jauset; Laura Soucek; Luis M. Montuenga; Manel Esteller; Eduard Monsó; Victor Ivo Peinado; Pere Gascon; Cristina Fillat; Frank Hilberg; Noemí Reguart; Jordi Alcaraz

    The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAF) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non–small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC. Here we show that tumor fibrosis is actually higher in ADC-TAFs than SCC-TAFs in vitro and patient samples. Mechanistically, the reduced fibrosis and nintedanib response of SCC-TAFs was associated with increased promoter methylation of the profibrotic TGFβ transcription factor SMAD3 compared with ADC-TAFs, which elicited a compensatory increase in TGFβ1/SMAD2 activation. Consistently, forcing global DNA demethylation of SCC-TAFs with 5-AZA rescued TGFβ1/SMAD3 activation, whereas genetic downregulation of SMAD3 in ADC-TAFs and control fibroblasts increased TGFβ1/SMAD2 activation, and reduced their fibrotic phenotype and antitumor responses to nintedanib in vitro and in vivo . Our results also support that smoking and/or the anatomic location of SCC in the proximal airways, which are more exposed to cigarette smoke particles, may prime SCC-TAFs to stronger SMAD3 epigenetic repression, because cigarette smoke condensate selectively increased SMAD3 promoter methylation. Our results unveil that the histotype-specific regulation of tumor fibrosis in lung cancer is mediated through differential SMAD3 promoter methylation in TAFs and provide new mechanistic insights on the selective poor response of SCC-TAFs to nintedanib. Moreover, our findings support that patients with ADC may be more responsive to antifibrotic drugs targeting their stromal TGFβ1/SMAD3 activation. Significance: This study implicates the selective epigenetic repression of SMAD3 in SCC-TAFs in the clinical failure of nintedanib in SCC and supports that patients with ADC may benefit from antifibrotic drugs targeting stromal TGFβ1/SMAD3.

    更新日期:2020-01-04
  • Highlights from Recent Cancer Literature
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    American Association for Cancer Research

    ![][1] MYC is critical for tumorigenesis, however, to date it remains untargetable. Han and colleagues utilized a pharmacophore-based in silico screening approach to validate in vitro and in vivo small molecules that disrupted MYC/MAX dimerization and DNA binding. Their lead compound

    更新日期:2020-01-04
  • Bernard Fisher, MD: In Memoriam (1918–2019)
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Nancy E. Davidson

    ![][1] With the death of Bernard Fisher, MD, on October 16, 2019, at the age of 101, we lost a visionary thinker and medical pioneer in cancer research and care. Fisher, a surgeon and clinical trialist, revolutionized breast cancer treatment, leading trials that transformed breast

    更新日期:2020-01-04
  • The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Catherine J. Libby; Jonathan McConathy; Victor Darley-Usmar; Anita B. Hjelmeland

    Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell–cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cancer stem cells in leukemia and gliomas. Similarly, defining metabolic heterogeneity and fuel-switching signals in nonneoplastic stem cells may also give important insights into the corresponding molecular mechanisms controlling metabolic plasticity in cancer. These advances are important, because metabolic adaptation to anticancer therapeutics is rooted in this inherent metabolic plasticity and is a therapeutic challenge to be overcome.

    更新日期:2020-01-04
  • Natural Killer Cell–Derived Vesicular miRNAs: A New Anticancer Approach?
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Muller Fabbri

    Natural killer (NK) cells are cytotoxic lymphocytes targeting virus-infected cells and cancer cells. Specific pro- and antikilling signals modulate the overall ability of NK cells to kill cancer cells, however, several immune-escape mechanisms can be enacted by cancer cells to avoid NK-mediated killing. Recently, increasing evidence has shown that extracellular vesicles (EV) released by NK cells carry proteins and miRNAs able to exert an antitumoral effect, even within a highly immune-suppressive tumor microenvironment. These recent findings suggest a possible use of NK-derived EVs as anticancer agents and propel the development of new strategies to enrich EVs with the most effective anticancer cargo as a promising new anticancer approach.

    更新日期:2020-01-04
  • Physical Activity and Breast Cancer: Focusing on High-Risk Subgroups and Putting Recommendations in Context
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Nicole M. Niehoff; Alexandra J. White; Dale P. Sandler

    While it is well-established that physical activity is associated with a decreased risk of breast cancer, most studies have been conducted in populations at an average underlying breast cancer risk. In this issue of Cancer Research , Kehm and colleagues present compelling evidence that adulthood physical activity is beneficial across the risk spectrum, including among women with BRCA1 and BRCA2 mutations. These findings are significant because women who are at a higher baseline risk are not engaging in sufficient physical activity to meet current guidelines but may be more motivated to do so knowing that they, like women in the general population, may benefit. See related article by Kehm et al., [p. 116][1] [1]: /lookup/volpage/80/116?iss=1

    更新日期:2020-01-04
  • Investigating New Mechanisms of Acquired Resistance to Targeted Therapies: If You Hit Them Harder, Do They Get Up Differently?
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Konstantinos V. Floros; Aaron N. Hata; Anthony C. Faber

    Targeted therapies have revolutionized treatment of several different types of cancers. However, in almost an invariable fashion, cancers eventually regrow in the presence of the targeted therapy, a phenomenon referred to as acquired resistance. In this issue of Cancer Research , Finn and colleagues demonstrate that modeling acquired resistance to MET tyrosine kinase inhibition in a MET -amplified gastric cancer cell line by a single, high exposure of the targeted therapy reveals clinically relevant acquired resistant mechanisms, which may be more faithful and comprehensive than the ones revealed through traditional ramp-up approaches. See related article by Finn et al., [p. 79][1] [1]: /lookup/volpage/80/79?iss=1

    更新日期:2020-01-04
  • Novel Mechanisms of Cancer Emerge When Accounting for Sex as a Biological Variable
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Melissa A. Wilson; Kenneth H. Buetow

    There is a large gap between the aspiration of considering sex as biological variable and the execution of such studies, particularly in genomic studies of human cancer. This represents a lost opportunity to identify sex-specific molecular etiologies that may underpin the dramatic sex differences in cancer incidence and outcome. There are conceptual and practical challenges associated with considering sex as a biological variable, including the definition of sex itself and the need for novel study designs. A better understanding of cancer mechanisms, resulting in improved outcomes, will reward the effort invested in incorporating sex as a biological variable.

    更新日期:2020-01-04
  • MET Inhibition Elicits PGC1α-Dependent Metabolic Reprogramming in Glioblastoma
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Yiru Zhang; Trang T.T. Nguyen; Enyuan Shang; Angeliki Mela; Nelson Humala; Aayushi Mahajan; Junfei Zhao; Chang Shu; Consuelo Torrini; Maria J. Sanchez-Quintero; Giulio Kleiner; Elena Bianchetti; Mike-Andrew Westhoff; Catarina M. Quinzii; Georg Karpel-Massler; Jeffrey N. Bruce; Peter Canoll; Markus D. Siegelin

    The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-glucose, U-13C-glutamine, and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. Significance: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.

    更新日期:2020-01-04
  • Phosphorylation of RAB7 by TBK1/IKKε Regulates Innate Immune Signaling in Triple-Negative Breast Cancer
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Jessica L. Ritter; Zehua Zhu; Tran C. Thai; Navin R. Mahadevan; Philipp Mertins; Erik H. Knelson; Brandon P. Piel; Saemi Han; Jacob D. Jaffe; Steven A. Carr; David A. Barbie; Thanh U. Barbie

    Triple-negative breast cancer (TNBC) is a heterogeneous disease enriched for mutations in PTEN and dysregulation of innate immune signaling. Here, we demonstrate that Rab7, a recently identified substrate of PTEN phosphatase activity, is also a substrate of the innate immune signaling kinases TANK-binding kinase 1 (TBK1)/IκB kinase ε (IKKε) on the same serine-72 (S72) site. An unbiased search for novel TBK1/IKKε substrates using stable isotope labeling with amino acids in cell culture phosphoproteomic analysis identified Rab7-S72 as a top hit. PTEN-null TNBC cells expressing a phosphomimetic version of Rab7-S72 exhibited diffuse cytosolic Rab7 localization and enhanced innate immune signaling, in contrast to a kinase-resistant version, which localized to active puncta that promote lysosomal-mediated stimulator of interferon genes (STING) degradation. Thus, convergence of PTEN loss and TBK1/IKKε activation on Rab7-S72 phosphorylation limited STING turnover and increased downstream production of IRF3 targets including CXCL10, CCL5, and IFNβ. Consistent with this data, PTEN-null TNBC tumors expressed higher levels of STING, and PTEN-null TNBC cell lines were hyperresponsive to STING agonists. Together, these findings begin to uncover how innate immune signaling is dysregulated downstream of TBK1/IKKε in a subset of TNBCs and reveals previously unrecognized cross-talk with STING recycling that may have implications for STING agonism in the clinic. Significance: These findings identify Rab7 as a substrate for TBK1 for regulation of innate immune signaling, thereby providing important insight for strategies aimed at manipulating the immune response to enhance therapeutic efficacy in TNBC.

    更新日期:2020-01-04
  • Heparanase and Chemotherapy Synergize to Drive Macrophage Activation and Enhance Tumor Growth
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Udayan Bhattacharya; Lilach Gutter-Kapon; Tal Kan; Ilanit Boyango; Uri Barash; Shi-Ming Yang; JingJing Liu; Miriam Gross-Cohen; Ralph D. Sanderson; Yuval Shaked; Neta Ilan; Israel Vlodavsky

    The emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized, encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here, we focused on the cross-talk between macrophages, chemotherapy, and heparanase and the combined effect on tumor progression. Macrophages were markedly activated by chemotherapeutics paclitaxel and cisplatin, evidenced by increased expression of proinflammatory cytokines, supporting recent studies indicating that chemotherapy may promote rather than suppress tumor regrowth and spread. Strikingly, cytokine induction by chemotherapy was not observed in macrophages isolated from heparanase-knockout mice, suggesting macrophage activation by chemotherapy is heparanase dependent. paclitaxel-treated macrophages enhanced the growth of Lewis lung carcinoma tumors that was attenuated by a CXCR2 inhibitor. Mechanistically, paclitaxel and cisplatin activated methylation of histone H3 on lysine 4 (H3K4) in wild-type but not in heparanase-knockout macrophages. Furthermore, the H3K4 presenter WDR5 functioned as a molecular determinant that mediated cytokine induction by paclitaxel. This epigenetic, heparanase-dependent host-response mechanism adds a new perspective to the tumor-promoting functions of chemotherapy, and offers new treatment modalities to optimize chemotherapeutics. Significance: Chemotherapy-treated macrophages are activated to produce proinflammatory cytokines, which are blunted in the absence of heparanase.

    更新日期:2020-01-04
  • Suppression of LIM Kinase 1 and LIM Kinase 2 Limits Glioblastoma Invasion
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Joseph Chen; Badriprasad Ananthanarayanan; Kelsey S. Springer; Kayla J. Wolf; Sharon M. Sheyman; Vivien D. Tran; Sanjay Kumar

    The aggressive brain tumor glioblastoma (GBM) is characterized by rapid cellular infiltration of brain tissue, raising the possibility that disease progression could potentially be slowed by disrupting the machinery of cell migration. The LIM kinase isoforms LIMK1 and LIMK2 (LIMK1/2) play important roles in cell polarization, migration, and invasion and are markedly upregulated in GBM and many other infiltrative cancers. Yet, it remains unclear whether LIMK suppression could serve as a viable basis for combating GBM infiltration. In this study, we investigated effects of LIMK1/2 suppression on GBM invasion by combining GBM culture models, engineered invasion paradigms, and mouse xenograft models. While knockdown of either LIMK1 or LIMK2 only minimally influenced invasion in culture, simultaneous knockdown of both isoforms strongly reduced the invasive motility of continuous culture models and human GBM tumor-initiating cells (TIC) in both Boyden chamber and 3D hyaluronic acid spheroid invasion assays. Furthermore, LIMK1/2 functionally regulated cell invasiveness, in part, by disrupting polarized cell motility under confinement and cell chemotaxis. In an orthotopic xenograft model, TICs stably transduced with LIMK1/2 shRNA were implanted intracranially in immunocompromised mice. Tumors derived from LIMK1/2 knockdown TICs were substantially smaller and showed delayed growth kinetics and more distinct margins than tumors derived from control TICs. Overall, LIMK1/2 suppression increased mean survival time by 30%. These findings indicate that LIMK1/2 strongly regulate GBM invasive motility and tumor progression and support further exploration of LIMK1/2 as druggable targets. Significance: Targeting the actin-binding proteins LIMK1 and LIMK2 significantly diminishes glioblastoma invasion and spread, suggesting the potential value of these proteins as therapeutic targets.

    更新日期:2020-01-04
  • A Single-Step, High-Dose Selection Scheme Reveals Distinct Mechanisms of Acquired Resistance to Oncogenic Kinase Inhibition in Cancer Cells
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Kenneth J. Finn; Scott E. Martin; Jeff Settleman

    Despite the remarkable clinical efficacy demonstrated by molecularly targeted cancer therapeutics, the benefits are typically temporary due to the emergence of acquired drug resistance. This has spurred a massive effort by the cancer research community to identify mechanisms used by cancer cells to evade treatment. Among the various methodologies developed and employed to identify such mechanisms, the most commonly used approach has been to model acquired resistance by exposing cancer cells in culture to gradually increasing concentrations of drug over an extended period of time. Here, we employed a less commonly used variation on this approach, wherein resistant cells are selected by immediately exposing cancer cells to a continuous, high concentration of drug. Using this approach, we isolated clones representing three distinct mechanisms of resistance to inhibition of MET kinase activity from a single clonally derived cancer cell line. The emergent clones had acquired resistance through engagement of alternative receptor tyrosine kinases either through upregulation of FGF3 or HBEGF or increased MAPK signaling through an activating V600E mutation in BRAF. Importantly, these mechanisms were not identified using the conventional “ramp-up” approach in previous studies that employed the same cell line. These results suggest that the particular nature of the selection scheme employed in cell culture modeling studies can determine which potential resistance mechanisms are identified and which ones may be missed, highlighting the need for careful consideration of the specific approach used to model resistance in cultured cells. Significance: Through modeling resistance to MET kinase inhibition in cultured cancer cells using single-step, high-dose selection, these findings highlight that the specific nature of the selection protocol impacts which resistance mechanisms are identified. See related commentary by Floros et al., [p. 25][1] [1]: /lookup/volpage/80/25?iss=1

    更新日期:2020-01-04
  • Adhesion of T Cells to Endothelial Cells Facilitates Blinatumomab-Associated Neurologic Adverse Events
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Matthias Klinger; Gerhard Zugmaier; Virginie Nägele; Maria-Elisabeth Goebeler; Christian Brandl; Matthias Stelljes; Hans Lassmann; Arend von Stackelberg; Ralf C. Bargou; Peter Kufer

    Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell–independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell–dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro , and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. Significance: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.

    更新日期:2020-01-04
  • Targeting Novel Sodium Iodide Symporter Interactors ADP-Ribosylation Factor 4 and Valosin-Containing Protein Enhances Radioiodine Uptake
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Alice Fletcher; Martin L. Read; Caitlin E.M. Thornton; Dean P. Larner; Vikki L. Poole; Katie Brookes; Hannah R. Nieto; Mohammed Alshahrani; Rebecca J. Thompson; Gareth G. Lavery; Iñigo Landa; James A. Fagin; Moray J. Campbell; Kristien Boelaert; Andrew S. Turnell; Vicki E. Smith; Christopher J. McCabe

    The sodium iodide symporter (NIS) is required for iodide uptake, which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer, where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined. Here, we used tandem mass spectrometry followed by coimmunoprecipitation and proximity ligation assays to identify and validate two key nodes—ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP)—controlling NIS trafficking. Using cell-surface biotinylation assays and highly inclined and laminated optical sheet microscopy, we demonstrated that ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP—a principal component of endoplasmic reticulum (ER)–associated degradation—governed NIS proteolysis. Gene expression analysis indicated VCP expression was particularly induced in aggressive thyroid cancers and in patients who had poorer outcomes following RAI treatment. Two repurposed FDA-approved VCP inhibitors abrogated VCP-mediated repression of NIS function, resulting in significantly increased NIS at the cell-surface and markedly increased RAI uptake in mouse and human thyroid models. Collectively, these discoveries delineate NIS trafficking and highlight the new possibility of systemically enhancing RAI therapy in patients using FDA-approved drugs. Significance: These findings show that ARF4 and VCP are involved in NIS trafficking to the plasma membrane and highlight the possible therapeutic role of VCP inhibitors in enhancing radioiodine effectiveness in radioiodine-refractory thyroid cancer.

    更新日期:2020-01-04
  • Recreational Physical Activity Is Associated with Reduced Breast Cancer Risk in Adult Women at High Risk for Breast Cancer: A Cohort Study of Women Selected for Familial and Genetic Risk
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    Rebecca D. Kehm; Jeanine M. Genkinger; Robert J. MacInnis; Esther M. John; Kelly-Anne Phillips; Gillian S. Dite; Roger L. Milne; Nur Zeinomar; Yuyan Liao; Julia A. Knight; Melissa C. Southey; Wendy K. Chung; Graham G. Giles; Sue-Anne McLachlan; Kristen D. Whitaker; Michael Friedlander; Prue C. Weideman; Gord Glendon; Stephanie Nesci; kConFab Investigators; Irene L. Andrulis; Saundra S. Buys; Mary B. Daly; John L. Hopper; Mary Beth Terry

    Although physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort, which is enriched with women who have a breast cancer family history ( N = 15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest four quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR, 0.80; 95% confidence interval, 0.68–0.93). The association was not modified by familial risk or BRCA mutation status ( P interactions >0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk. Significance: These findings suggest that physical activity might reduce breast cancer risk by about 20% for women across the risk continuum, including women at higher-than-average risk due to their family history or genetic susceptibility. See related commentary by Niehoff et al., [p. 23][1] [1]: /lookup/volpage/80/23?iss=1

    更新日期:2020-01-04
  • Acknowledgment to Reviewers
    Cancer Res. (IF 8.378) Pub Date : 2020-01-01
    American Association for Cancer Research

    The Cancer Research editors wish to acknowledge with sincere appreciation the assistance of the following reviewers who have generously contributed their time and effort during the past year[1][1] in the appraisal of manuscripts. These reviewers have been enormously helpful in assessing the merit of

    更新日期:2020-01-04
  • Unshielding multidrug resistant cancer through selective iron depletion of P-glycoprotein expressing cells
    Cancer Res. (IF 8.378) Pub Date : 2019-12-30
    Mihály Cserepes; Dóra Türk; Szilárd Tóth; Veronika F.S. Pape; Anikó Gaál; Melinda Gera; Judit Eszter Szabó; Nóra Kucsma; György Várady; Beáta G. Vértessy; Christina Streli; Pál Tamás Szabó; Jozsef Tovari; Norbert Szoboszlai; Gergely Szakács

    Clinical evidence shows that following initial response to treatment drug-resistant cancer cells frequently evolve and eventually most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366-iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance.

    更新日期:2019-12-30
  • Aurora A kinase inhibition destabilizes PAX3-FOXO1 and MYCN and synergizes with Navitoclax to induce Rhabdomyosarcoma cell death
    Cancer Res. (IF 8.378) Pub Date : 2019-12-30
    Johannes Ommer; Joanna L Selfe; Marco Wachtel; Eleanor M O'Brien; Dominik Laubscher; Michaela Roemmele; Stephanie Kasper; Olivier Delattre; Didier Surdez; Gemma Petts; Anna Kelsey; Janet Shipley; Beat W Schäfer

    The clinically aggressive alveolar rhabdomyosarcoma subtype is characterized by expression of the oncogenic fusion protein PAX3-FOXO1, which is critical for tumorigenesis and cell survival. Here we studied the mechanism of cell death induced by loss of PAX3-FOXO1 expression and identified a novel pharmacological combination therapy that interferes with PAX3-FOXO1 biology at different levels. Depletion of PAX3-FOXO1 in fusion positive (FP)-RMS cells induced intrinsic apoptosis in a NOXA-dependent manner. This was pharmacologically mimicked by the BH3 mimetic navitoclax, identified as a top compound in a screen of 208 targeted compounds. In a parallel approach, and to identify drugs that alter the stability of PAX3-FOXO1 protein, the same drug library was screened and fusion protein levels were directly measured as a read-out. This revealed that inhibition of Aurora kinase A most efficiently negatively affected PAX3-FOXO1 protein levels. Interestingly, this occurred through a novel specific phosphorylation event in and binding to the fusion protein. Aurora kinase A inhibition also destabilized MYCN, which is both a functionally important oncogene and transcriptional target of PAX3-FOXO1. Combined treatment with an Aurora kinase A inhibitor and navitoclax in FP-RMS cell lines and patient-derived xenografts synergistically induced cell death and significantly slowed tumor growth. These studies identify a novel functional interaction of Aurora kinase A with both PAX3-FOXO1 and its effector MYCN, and reveal new opportunities for targeted combination treatment of FP-RMS.

    更新日期:2019-12-30
  • Wnt-Induced Stabilization of KDM4C Is Required for Wnt/β-Catenin Target Gene Expression and Glioblastoma Tumorigenesis
    Cancer Res. (IF 8.378) Pub Date : 2019-12-30
    Yaohui Chen; Runping Fang; Chen Yue; Guoqiang Chang; Peng Li; Qing Guo; Jing Wang; Aidong Zhou; Sicong Zhang; Gregory N Fuller; Xiaobing Shi; Suyun Huang

    Wnt/β-catenin signaling activates the transcription of target genes to regulate stem cells and cancer development. However, the contribution of epigenetic regulation to this process is unknown. Here, we report that Wnt activation stabilizes the epigenetic regulator KDM4C that promotes tumorigenesis and survival of human glioblastoma cells by epigenetically activating the transcription of Wnt target genes. KDM4C protein expression was upregulated in human glioblastomas and its expression directly correlated with Wnt activity and Wnt target gene expression. KDM4C was essential for Wnt-induced gene expression and tumorigenesis of glioblastoma cells. In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation. Wnt3a stabilized KDM4C through inhibition of GSK3-dependent protein kinase R activity. Stabilized KDM4C accumulated in the nucleus and bound to and demethylated TCF4-associated histone H3K9 by interacting with β-catenin, promoting HP1γ removal and transcriptional activation. These findings reveal that Wnt-KDM4C-β-catenin signaling represents a novel mechanism for the transcription of Wnt target genes and regulation of tumorigenesis with important clinical implications.

    更新日期:2019-12-30
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