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  • ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas
    bioRxiv. Cancer Biol. Pub Date : 2021-01-15
    Lucie Darmusey; Gaëlle Pérot; Noémie Thébault; Sophie Le Guellec; Nelly Desplat; Laëtitia Gaston; Lucile Delespaul; Tom Lesluyes; Elodie Darbo; Anne Gomez-Brouchet; Elodie Richard; Jessica Baud; Laura Leroy; Jean Michel Coindre; Jean-Yves Blay; Frédéric Chibon

    Whole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas revealed ATRX to be one of the most frequently mutated genes in leiomyosarcomas after TP53 and RB1. While its function is well described in the alternative lengthening of telomeres mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression

    更新日期:2021-01-15
  • Post-transcriptional gene regulation by the RNA binding protein IGF2BP3 is critical for MLL-AF4 mediated leukemogenesis
    bioRxiv. Cancer Biol. Pub Date : 2021-01-14
    Tiffany M Tran; Julia Philipp; Jaspal Bassi; Neha Nibber; Jolene Draper; Tasha Lin; Jayanth Kumar Palanichamy; Amit Kumar Jaiswal; Oscar Silva; May Paing; Jennifer King; Sol Katzman; Jeremy R Sanford; Dinesh S Rao

    Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes and a high risk of relapse. Here, we found that MLL-AF4, the most common MLL fusion protein in patients, transcriptionally induces IGF2BP3 and that IGF2BP3 strongly amplifies MLL-Af4 mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4 driven

    更新日期:2021-01-15
  • Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer
    bioRxiv. Cancer Biol. Pub Date : 2021-01-14
    Daniel Cui Zhou; Reyka G. Jayasinghe; John M. Herndon; Erik Storrs; Chia-Kuei Mo; Yige Wu; Robert S. Fulton; Matthew A. Wyczalkowski; Catrina C. Fronick; Lucinda A. Fulton; Lisa Thammavong; Kazuhito Sato; Houxiang Zhu; Hua Sun; Liang-Bo Wang; Yize Li; Chong Zuo; Joshua F. McMichael; Sherri R. Davies; Elizabeth L. Appelbaum; Keenan J. Robbins; Sara E. Chasnoff; Xiaolu Yang; Ruiyang Liu; Ashley N. Reeb;

    Pancreatic Ductal Adenocarcinoma (PDAC) is a lethal disease with limited treatment options and poor survival. We studied 73 samples from 21 patients (7 treatment-naive and 14 treated with neoadjuvant regimens), analyzing distinct spatial units and performing bulk proteogenomics, single cell sequencing, and cellular imaging. Spatial drivers, including mutant KRAS, SMAD4, and GNAQ, were associated with

    更新日期:2021-01-15
  • A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment
    bioRxiv. Cancer Biol. Pub Date : 2021-01-14
    Lindsay B Alcaraz; Aude Mallavialle; Timothee David; Danielle Derocq; Frederic Delolme; Cindy Dieryckx; Florence Boissiere-Michot; Joelle Simony-Lafontaine; Stanislas Du Manoir; Pitter Huesgen; Christopher M Overall; Sophie Tartare-Deckert; William Jacot; Thierry Chardes; Severine Guiu; Pascal Roger; Thomas Reinheckel; Catherine Moali; Emmanuelle Liaudet-Coopman

    Extracellular matrix (ECM) remodeling by proteases results in the release of protein fragments that promote tumor progression and metastasis. The protease cathepsin D (cath-D), a marker of poor prognosis in triple-negative breast cancer (TNBC), is aberrantly secreted in the tumor microenvironment. Using degradomic analyses by TAILS, we discovered that the matricellular protein SPARC is a substrate

    更新日期:2021-01-14
  • Pre-metastatic niche drives breast cancer invasion by modulating MSC homing and CAF differentiation
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Neha Saxena; Garvit Bhardwaj; Sameer Jadhav; Hamim Zafar; Shamik Sen

    The extent to which cancer-associated alterations in extracellular matrix stiffness influences the crosstalk between cancer cells and mesenchymal stem cells (MSCs) remains unclear. By analyzing multiple single- cell RNA sequencing datasets, we establish the existence of a cell sub-population co-expressing MSC and cancer associated fibroblast (CAF) markers in highly aggressive triple-negative breast

    更新日期:2021-01-14
  • Raman spectroscopy on microcalcifications reveals peculiar differences between male and female breast cancer
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Alessandro Caldarone; Francesca Piccotti; Carlo Morasso; Marta Truffi; Federico Sottotetti; Chiara Guerra; Sara Albasini; Manuela Agozzino; Laura Villani; Fabio Corsi

    Microcalcifications (MCs) are important disease markers for breast cancer. Many studies were conducted on their characterization in female breast cancer (FBC), but no information is available on their composition in male breast cancer (MBC). Raman spectroscopy (RS) is a molecular spectroscopy technique that can explore the biochemical composition of MCs rapidly and without requiring any staining protocol

    更新日期:2021-01-14
  • Diet induced hyperlipidemia confers resistance to standard therapy in pancreatic cancer by selecting for "tumor protective" microbial metabolites and treatment refractory cells.
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Kousik Kesh; Roberto Mendez; Beatriz Mateo-Victoriano; Vanessa T Garrido; Brittany Durden; Vineet K Gupta; Alfredo Oliveras Reyes; Jashodeep Datta; Nipun Merchant; Santanu Banerjee; Sulagna Banerjee

    Obesity causes a number of systemic alterations including chronic inflammation and changes in gut microbiome. However, whether these actively contribute to poor survival and therapy resistance in patients with pancreatic cancer remain undetermined. Our current study shows that high fat diet fed pancreatic tumor bearing mice do not respond to standard of care therapy with gemcitabine and paclitaxel

    更新日期:2021-01-14
  • A potent tumour-suppressor TCF11, than its prototypic Nrf1α, is defined by similar yet different regulatory profiles of both isoforms, with a striking disparity from Nrf2
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Meng Wang; Yonggang Ren; Shaofan Hu; Keli Liu; Lu Qiu; Yiguo Zhang

    Nrf1 and Nrf2, as two principal CNC-bZIP transcription factors, regulate similar but different targets involved in a variety of biological functions for maintaining cell homeostasis and organ integrity. Of note, the unique topobiological behavior of Nrf1 makes its functions more complicated than Nrf2, because it is allowed for alternatively transcribing and selectively splicing to yield multiple isoforms

    更新日期:2021-01-14
  • BRN2 is a non-canonical melanoma tumor-suppressor
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Michael Hamm; Pierre Sohier; Valerie Petit; Jeremy Raymond; Veronique Delmas; Madeleine Le Coz; Franck Gesbert; Colin Kenny; Zackie Aktary; Marie Pouteaux; Florian Rambow; Alain Sarasin; Alfonso Bellacosa; Luis Sanchez-del-Campo; Laura Mosteo; Martin Lauss; Dies Meijer; Eirikur Steingrimsson; Goran Jonsson; Robert Cornell; Irwin Davidson; Colin Goding; Lionel Larue

    While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown

    更新日期:2021-01-14
  • Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Jennifer E Kay; Joshua J Corrigan; Amanda L Armijo; Ilana S Nazari; Ishwar N Kohale; Dorothea K Torous; Svetlana L Avlasevich; Robert G Croy; Dushan N Wadduwage; Sebastian E Carrasco; Stephen D Dertinger; Forest M White; John M Essigmann; Leona D Samson; Bevin P Engelward

    N-nitrosodimethylamine (NDMA) is a DNA methylating agent that has been discovered to contaminate water, food and drugs. The alkyladenine glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we studied Aag-/- and Aag-overexpressing mice that harbor increased levels of either replication-blocking

    更新日期:2021-01-14
  • ARID1A-mutant and deficient bladder cancer is sensitive to EZH2 pharmacologic inhibition
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    James E Ferguson; Hasibur Rehman; Darshan Shimoga Chandrashekar; Balabhadrapatruni Chakravarthi; Saroj Nepal; Marie-Lisa Eich; Alyncia Robinson; Sumit Agarwal; Sai Akshaya Hodigere Balasubramanya; Gurudatta Naik; Upender Manne; George Netto; Chong-xian Pan; Guru Sonpavde; Sooryanarayana Varambally

    Metastatic urothelial carcinoma of the bladder is generally incurable by current systemic therapy. Molecular characterization of bladder cancer (BLCa) has revealed multiple candidate driver genes for BLCa tumorigenesis. Epigenetic/chromatin modifiers have been shown to be frequently mutated in BLCa, with ARID1A mutations highly prevalent in nearly 20% of early and late stage tumors. EZH2 is a histone

    更新日期:2021-01-14
  • iRGD-liposomes enhance tumor delivery and therapeutic efficacy of antisense oligonucleotide drugs against primary prostate cancer and bone metastasis
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Jibin Guan; Hong Guo; Tang Tang; Yihan Wang; Yushuang Wei; Punit Seth; Yingming Li; Scott M Dehm; Erkki Ruoslahti; Hong-Bo Pang

    Nucleotide-based drugs, such as antisense oligonucleotides (ASOs), have unique advantages in treating human diseases as they provide virtually unlimited ability to target any gene. However, their clinical translation faces many challenges, one of which is poor delivery to the target tissue in vivo. This problem is particularly evident in solid tumors. Here, we functionalized liposomes with a tumor-homing

    更新日期:2021-01-14
  • Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Cecile Thirant; Agathe Peltier; Simon Durand; Amira Kramdi; Caroline Louis-Brennetot; Cecile Pierre-Eugene; Ana Costa; Amandine Grelier; Sakina Zaidi; Nadege Gruel; Irene Jimenez; Eve Lapouble; Gaelle Pierron; Herve Brisse; Arnaud Gauthier; Paul Freneaux; Sandrine Grossetete-Lalami; Laura G Baudrin; Virginie Raynal; Sylvain Baulande; Angela Bellini; Jaydutt Bhalshankar; Angel M Carcaboso; Birgit Geoerger;

    Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain poorly defined. Here, we demonstrate that the knock-out of GATA3, but not of PHOX2A or PHOX2B, in noradrenergic cells induces

    更新日期:2021-01-14
  • Human colorectal pre-cancer atlas identifies distinct molecular programs underlying two major subclasses of pre-malignant tumors
    bioRxiv. Cancer Biol. Pub Date : 2021-01-13
    Bob Chen; Eliot T McKinley; Alan J Simmons; Marisol A Ramirez; Xiangzhu Zhu; Austin N Southard-Smith; Nicholas O. Markham; Quanhu Sheng; Julia Drewes; Yanwen Xu; Cody Nicholas Heiser; Yuan Zhou; Frank Revetta; Lynne D Berry; Wei Zheng; Mary Kay Washington; Qiuyin Cai; Cynthia L Sears; James R Goldenring; Jeffrey L Franklin; Simon Vandekar; Joseph T Roland; Timothy Su; Won Jae Huh; Qi Liu; Robert J

    Most colorectal cancers(CRCs) develop from either adenomas (ADs) or sessile serrated lesions (SSLs). The origins and molecular landscapes of these histologically distinct pre-cancerous polyps remain incompletely understood. Here, we present an atlas at single-cell resolution of sporadic conventional tubular/tubulovillous ADs, SSLs, hyperplastic polyps (HPs), microsatellite stable (MSS) and unstable

    更新日期:2021-01-13
  • Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-low Induction of Therapy Resistance
    bioRxiv. Cancer Biol. Pub Date : 2021-01-12
    Kellie A Cotter; John Gallon; Nadine Uebersax; Philip Rubin; Kate D. Meyer; Salvatore Piscuoglio; Samie R. Jaffrey; Mark A. Rubin

    Recent evidence has highlighted the role of N6-methyladenosine (m6A) in the regulation of mRNA expression, stability and translation, supporting a potential role for post- transcriptional regulation mediated by m6A in cancer. Here we explore prostate cancer as an exemplar and demonstrate that low levels of N6-adenosine-methyltransferase (METTL3) is associated with advanced metastatic disease. To explore

    更新日期:2021-01-13
  • Inhibition of polo-like kinase 1 (PLK1) facilitates reactivation of gamma-herpesviruses in B-cell lymphomas and their elimination
    bioRxiv. Cancer Biol. Pub Date : 2021-01-12
    Ayan Biswas; Guillaume N Fiches; Dawei Zhou; Zhenyu Wu; Xuefeng Liu; Qin Ma; Weiqiang Zhao; Jian Zhu; Netty G Santoso

    Both Kaposis sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) establish the persistent, life-long infection primarily at the latent status, and contribute to certain types of tumors, including B cell lymphomas, especially in immuno-compromised individuals, such as people living with HIV (PLWH). Lytic reactivation of these viruses can be employed to kill tumor cells harboring latently

    更新日期:2021-01-12
  • Unfolding the Apoptotic Mechanism of Antioxidant Enriched-Leaves of Tabebuia pallida in EAC Cells
    bioRxiv. Cancer Biol. Pub Date : 2021-01-11
    AHM Khurshid Alam; Md. Mahbubur Rahman; Muhammad Ali Khan; A. S. M. Ali Reza; Khaled Mahmud Sujon; Rokshana Sharmin; Mamunur Rashid; Md. Golam Sadik; Md. Abu Reza; Toshifumi Tsukahara; Ashik Mosaddik; Glenda C Gobe

    Targeting apoptosis is a promising approach to inhibit the abnormal cell proliferation of cancer progression. Existing anti-apoptotic drugs, many derived from chemical substances, have often failed to combat cancer development and progression. Therefore, identification of apoptosis-inducing anticancer agents from plant-derived sources has become a key aim in cancer research. The present study was designed

    更新日期:2021-01-12
  • DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and in response to immunotherapy
    bioRxiv. Cancer Biol. Pub Date : 2021-01-11
    Louise A Baldwin; Nenad Bartonicek; Jessica Yang; Sunny Z Wu; Niantao Deng; Daniel L Roden; Chia-Ling Chan; Ghamdan Al-Eryani; Alexander Swarbrick; Simon Junankar

    Cancers evade the immune system in order to grow or metastasise through the process of cancer immunoediting. While checkpoint inhibitor therapy has been effective for reactivating tumour immunity in some cancers, many solid cancers, including breast cancer, remain largely non-responsive. Understanding the way non-responsive cancers evolve to evade immunity, what resistance pathways are activated and

    更新日期:2021-01-11
  • Transcriptomic analyses of MYCN-regulated genes in anaplastic Wilms' tumour cell lines reveals oncogenic pathways and potential therapeutic vulnerabilities
    bioRxiv. Cancer Biol. Pub Date : 2021-01-11
    Marianna Szemes; Zsombor Melegh; Jacob Bellamy; Ji Hyun Park; Biyao Chen; Alexander Greenhough; Daniel Catchpoole; Karim Malik

    The MYCN proto-oncogene is deregulated in many cancers, most notably in neuroblastoma where MYCN gene amplification identifies a clinical subset with very poor prognosis. Gene expression and DNA analyses have also demonstrated over-expression of MYCN mRNA, as well as focal amplifications, copy number gains and presumptive change of function mutations of MYCN in Wilms tumours with poorer outcome, including

    更新日期:2021-01-11
  • Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition
    bioRxiv. Cancer Biol. Pub Date : 2021-01-11
    Liang Yan; Bo Tu; Jun Yao; Jing Gong; Alessandro Carugo; Christopher Bristow; Qiuyun Wang; Cihui Zhu; Bingbing Dai; Yaan Kang; Leng Han; Ningping Feng; Yanqing Jin; Jason Fleming; Timothy Heffernan; Wantong Yao; Haoqiang Ying

    Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets for tumor maintenance. This is especially challenging in the context of PDAC, in which activating mutations of KRAS oncogene (KRAS*) dominate the genetic landscape. By using an inducible KrasG12D-driven p53 deficient PDAC mouse

    更新日期:2021-01-11
  • VEGFA′s distal enhancer regulates its alternative splicing in CML
    bioRxiv. Cancer Biol. Pub Date : 2021-01-10
    Sara Dahan; Klil Cohen; Mercedes Dentata; Eden Engal; Ahmad Siam; Gillian Kay; Yotam Drier; Shlomo Elias; Maayan Salton

    Enhancer demethylation in leukemia and lymphoma was shown to lead to overexpression of genes which promote cancer characteristics. The vascular endothelial growth factor A (VEGFA) enhancer, located 157 Kb downstream of its promoter, is demethylated in chronic myeloid leukemia (CML). VEGFA has several alternative splicing isoforms with different roles in vascularization and cancer progression. Since

    更新日期:2021-01-11
  • COMPARE, an ultra-fast and robust suite for multiparametric screening, identifies phenotypic drug responses in acute myeloid leukemia
    bioRxiv. Cancer Biol. Pub Date : 2021-01-10
    Morteza Chalabi Hajkarim; Ella Karjalainen; Mikhail Osipovitch; Konstantinos Dimopoulos; Sandra Leigh Gordon; Francesca Ambri; Kasper Dindler Rasmussen; Kirsten Gronbaek; Kristian Helin; Krister Wennerberg; Kyoung Jae Won

    Multiparametric phenotypic screening of cells, for example assessing their responses to small molecules or knockdown/knockout of specific genes, is a powerful approach to understanding cellular systems and identifying potential new therapeutic strategies. However, automated tools for analyzing similarities and differences between a large number of tested conditions have not been readily available.

    更新日期:2021-01-11
  • Targeting EGFR in glioblastoma with a novel brain-penetrant small molecule EGFR-TKI
    bioRxiv. Cancer Biol. Pub Date : 2021-01-09
    Jing Ni; Yanzhi Wang; Qiwei Wang; Johann S. Bergholz; Tao Jiang; Thomas M. Roberts; Nathanael S. Gray; Jean J. Zhao

    Epidermal growth factor receptor (EGFR) is mutated or amplified in a majority of glioblastoma (GBM), and its mutation and focal amplification correlate with a more aggressive disease course. However, EGFR-directed tyrosine kinase inhibitors (TKIs) tested to date have yielded minimal clinical benefit. Here, we report a novel covalent EGFR-TKI, CM93, as a potential specific drug to target adult GBMs

    更新日期:2021-01-10
  • Dependency of LKB1-inactivated lung cancer on aberrant CRTC-CREB activation
    bioRxiv. Cancer Biol. Pub Date : 2021-01-09
    Xin Zhou; Jennifer W. Li; Zirong Chen; Wei Ni; Xuehui Li; Rongqiang Yang; Huangxuan Shen; Jian Liu; Francesco J DeMayo; Jianrong Lu; Frederic J Kaye; Lizi Wu

    Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1-deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain

    更新日期:2021-01-10
  • Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival
    bioRxiv. Cancer Biol. Pub Date : 2021-01-09
    Jin-Hua Liang; Chong Wang; Stephanie Pei Tung Yiu; Bo Zhao; Rui Guo; Benjamin Gewurz

    Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5' triphosphate synthase 1 (CTPS1) suppress cell mediated immunity, resulting in fulminant EBV infection and EBV+ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA

    更新日期:2021-01-10
  • Pin Electrode Reactor: A novel cold atmospheric plasma device and its potential in glioblastoma treatment
    bioRxiv. Cancer Biol. Pub Date : 2021-01-09
    Andressa Maria deCarvalho; Sean Behan; Laurence Scally; Chaitanya Sarangapani; Renee Malone; Patrick Cullen; Brijesh Tiwari; James F Curtin

    Glioblastoma multiforme (GBM) is the most common and biologically aggressive brain tumour. The current standard therapy for GBM consists in surgical resection, followed by radiotherapy and chemotherapy. Yet, the treatment is limited due to the area for the surgical resection and for the inability of some drugs to cross the brain blood barrier, leading to a general prognostic of no more than a year

    更新日期:2021-01-10
  • Evaluating the transcriptional fidelity of cancer models
    bioRxiv. Cancer Biol. Pub Date : 2021-01-09
    Da Peng; Rachel Gleyzer; Wen-Hsin Tai; Pavithra Kumar; Qin Bian; Bradley Issacs; Edroaldo Lummertz da Rocha; Stephanie Cai; Kathleen DiNapoli; Franklin Huang; Patrick Cahan

    Background: Cancer researchers use cell lines, patient derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derives from the fidelity with which it represents the tumor type under investigation, however, the extent to which this is true is often unclear. The preponderance of models and the ability

    更新日期:2021-01-10
  • A Phylogenetic Approach to Inferring the Order in Which Mutations Arise during Cancer Progression
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Yuan Gao; Jeff Gaither; Julia Chifman; Laura Kubatko

    Although the role of evolutionary processes in cancer progression is widely accepted, increasing attention is being given to evolutionary mechanisms that can lead to differences in clinical outcome. Recent studies suggest that the temporal order in which somatic mutations accumulate during cancer progression is important. Single-cell sequencing provides a unique opportunity to examine the mutation

    更新日期:2021-01-10
  • Cysteine is a limiting factor for glioma proliferation and survival
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Mioara Larion; Victor Ruiz-Rodado; Tyrone Dowdy; Adrian Lita; Tamalee Kramp; Meili Zhang; Jinkyu Jung; Ana Dios-Esponera; Christel C. Herold-Mende; Kevin Camphausen; Mark R Gilbert

    Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of tumor dependence on external sources for some nutrients. We report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. 13C-tracing and the analysis of cystathionine synthase and cystathioninase levels revealed the metabolic landscape attributable

    更新日期:2021-01-10
  • Somatic mutations in CTCF zinc fingers produce cellular phenotypes explained by structure-function relationships
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    John EJ Rasko; Charles Geoffrey Bailey; Shailendra Gupta; Cynthia Metierre; Punkaja Amarasekera; Patrick O'Young; Wunna Kyaw; Tatyana Laletin; Habib Francis; Crystal Semaan; Krishna Singh; Charles Mullighan; Olaf Wolkenhauer; Ulf Schmitz

    Background: Human cancers commonly contain mutations in transcription factors that lead to aberrant DNA binding or altered effector function at target sites. One such factor significantly mutated in cancer is the evolutionarily-conserved CCCTC-binding factor (CTCF), which has fundamental roles in maintaining chromatin architecture and transcriptional regulation. Numerous cancer genome sequencing and

    更新日期:2021-01-10
  • HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Satoshi Takahashi; Akinori Kanai; Hiroshi Okuda; Ryo Miyamoto; Takeshi Kawamura; Hirotaka Matsui; Toshiya Inaba; Akifumi Takaori-Kondo; Akihiko Yokoyama

    Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism of aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their TRX2 domain. Among many MLL fusions, MLL-ELL particularly

    更新日期:2021-01-10
  • Cancer phylogenetics using single-cell RNA-seq data
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Jiri C. Moravec; Robert Lanfear; David Spector; Sarah Diermeier; Alex Gavryushkin

    Phylogenetic methods are emerging as an useful tool to understand cancer evolutionary dynamics, including tumor structure, heterogeneity, and progression. Most currently used approaches utilize either bulk whole genome sequencing (WGS) or single-cell DNA sequencing (scDNA-seq) and are based on calling copy number alterations and single nucleotide variants (SNVs). Here we explore the potential of single-cell

    更新日期:2021-01-10
  • GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Anna Mukha; Ugur Kahya; Annett Linge; Oleg Chen; Steffen Lock; Vasyl Lukiyanchuk; Susan Richter; Tiago C Alves; Mirko Peitzsch; Vladyslav Telychko; Sergej Skvortsov; Giulia Negro; Bertram Aschenbrenner; Ira-Ida Skvortsova; Peter Mirtschink; Fabian Lohaus; Tobias Holscher; Hans Neubauer; Mahdi Rivandi; Andre Franken; Bianca Behrens; Nikolas H Stoecklein; Marieta Toma; Ulrich Sommer; Sebastian Zschaeck;

    Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy

    更新日期:2021-01-10
  • Multiplexed Imaging Analysis of the Tumor-Immune Microenvironment Reveals Predictors of Outcome in Triple-Negative Breast Cancer
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Aalok N Patwa; Rikiya Yamashita; Jin Long; Leeat Keren; Michael Angelo; Daniel Rubin

    Triple-negative breast cancer (TNBC), the poorest-prognosis breast cancer subtype, lacks clinically approved biomarkers for patient risk stratification, treatment management, and immunotherapies. Prior literature has shown that interrogation of the tumor-immune microenvironment (TIME) may be a promising approach for the discovery of novel biomarkers that can fill these gaps. Recent developments in

    更新日期:2021-01-10
  • Single cell proteomics of tumor compartments identifies differential kinase activities defining sensitivity to mTOR-PI3-kinase inhibition
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Nezihi Murat Karabacak; Yu Zheng; Taronish D. Dubash; Risa Burr; Douglas S. Micalizzi; Ben S. Wittner; Devon F. Wiley; Valentine Comaills; Erin Emmons; Kira Niederhoffer; Uyen Ho; Linda Nieman; Wilhelm Haas; Shannon L. Stott; David T. Ting; David T. Miyamoto; Daniel A. Haber; Mehmet Toner; Shyamala Maheswaran

    Cancer therapy often results in heterogeneous responses in different metastatic lesions in the same patient. Inter- and intra-tumor heterogeneity in proteomic signaling within the various tumor compartments and its impact on therapy are not well characterized due to the limited sensitivity of single cell proteomic approaches. To overcome this barrier, we applied single cell mass cytometry with a customized

    更新日期:2021-01-10
  • Mapping cellular subpopulations within triple negative breast cancer tumors provides a tool for cancer sensitization to radiotherapy
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Heba Alkhatib; Ariel M. Rubinstein; Swetha Vasudevan; Efrat Flashner-Abramson; Shira Stefansky; Solomon Oguche; Tamar Peretz-Yablonsky; Avital Granit; Zvika Granot; Ittai Ben-Porath; Kim Sheva; Amichay Meirovitz; Nataly Kravchenko-Balasha

    Triple negative breast cancer (TNBC) is an aggressive type of cancer that is known to be resistant to radiotherapy (RT). Evidence is accumulating that is indicative of the plasticity of TNBC, where one cancer subtype switches to another in response to various treatments, including RT. In this study we aim to overcome tumor resistance by designing TNBC-sensitizing targeted therapies that exploit the

    更新日期:2021-01-10
  • Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Yang-Yang Ding; Hannah Kim; Kellyn Madden; Joseph P Loftus; Gregory M Chen; David Hottman Allen; Ruitao Zhang; Jason Xu; Yuxuan Hu; Sarah K Tasian; Kai Tan

    Systems biology approaches can identify critical targets in complex cancer signaling networks to inform therapy combinations and overcome conventional treatment resistance. Herein, we developed a data-driven, network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a high-risk leukemia subtype

    更新日期:2021-01-10
  • Multiomics Integration Elucidates Metabolic Modulators of Drug Resistance in Lymphoma
    bioRxiv. Cancer Biol. Pub Date : 2021-01-08
    Fouad Choueiry; Satishkumar Singh; Xiaowei Sun; Shiqi Zhang; Anuvrat Sircar; Hart Amber; Lapo Alinari; Epperla Narendranath; Robert Baiocchi; Jiangjiang Zhu; Lalit Sehgal

    Background Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton’s tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug tolerant form. The drug tolerant clones proliferate faster,

    更新日期:2021-01-10
  • A syntenin-deficient microenvironment educates AML for aggressiveness
    bioRxiv. Cancer Biol. Pub Date : 2021-01-07
    Raphael Leblanc; Joanna Fares; Armelle Goubard; Remy Castellano; Luc Camoin; Marielle Balzano; Rania Ghossoub; Berna Bou-Tayet; Cyril Fauriat; Norbert Vey; Jean-Paul Borg; Yves Collette; Michel Aurrand-Lions; Guido David; Pascale Zimmermann

    In acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify

    更新日期:2021-01-08
  • An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression
    bioRxiv. Cancer Biol. Pub Date : 2021-01-07
    Raffaella Sordella; Debjani Pal; Polona Safaric Tepes; Trine Lindsted; Ingrid Ibarra; Amaia Lujambio; Vilma Jimenez Sabinina; Serif Senturk; Madison Miller; Navya Korimerla; Jiahao Huang; Lawrence Glassman; Paul Lee; David Zeltsman; Kevin Hyman; Michael Esposito; Greg Hannon

    Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. Many lung cancer patients will develop resistance to chemotherapeutics. In the context of non-small cell lung cancers harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive Erlotinib resistance in certain tumors with mesenchymal-like

    更新日期:2021-01-08
  • Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma
    bioRxiv. Cancer Biol. Pub Date : 2021-01-06
    Tyler Risom; David Richard Glass; Candace C Liu; Belen Rivero-Gutierrez; Alex Baranski; Erin F McCaffrey; Noah F Greenwald; Adam C Kagel; Siri H Strand; Sushama Varma; Alex Kong; Leeat Keren; Sucheta Srivastava; Chunfang Zhu; Zumana Khair; Deborah J Veis; Katherine Deschryver; Sujay Vennam; Carlo Maley; E Shelley Hwang; Jeffrey R Marks; Sean C Bendall; Graham A Colditz; Robert B West; Michael Angelo

    Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand how the tumor microenvironment (TME) changes with transition to IBC, we used Multiplexed Ion Beam Imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to analyze 140 clinically annotated surgical resections covering the full spectrum of breast

    更新日期:2021-01-07
  • The H3K36me2 writer-reader dependency in H3K27M-DIPG
    bioRxiv. Cancer Biol. Pub Date : 2021-01-06
    Jia-Ray Yu; Gary LeRoy; Devin Bready; Joshua D Frenster; Ricardo Saldana-Meyer; Ying Jin; Nicolas Descostes; James M Stafford; Dimitris G Placantonakis; Danny Reinberg

    The lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, the placement of methylation at lysine 27 of histone H3 (H3K27me2/3)

    更新日期:2021-01-07
  • Cis-Regulatory Element Hijacking by Structural Variants Overshadows Topological Changes in Primary Prostate Cancer
    bioRxiv. Cancer Biol. Pub Date : 2021-01-06
    James R Hawley; Stanley Zhou; Christopher Arlidge; Giacomo Grillo; Ken Kron; Rupert Hugh-White; Theodorus van der Kwast; Michael Fraser; Paul C Boutros; Robert G Bristow; Mathieu Lupien

    Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional

    更新日期:2021-01-07
  • Misregulation of translation drives prostate cancer drug resistance
    bioRxiv. Cancer Biol. Pub Date : 2021-01-06
    Emeline I.J. Lelong; Pauline Adjibade; France-Helene Joncas; Valerie Grenier St-Sauveur; Jean-Philippe Lambert; Paul Toren; Rachid Mazroui; Samer M.I. Hussein

    Emerging evidence associates translation factors and regulators to tumorigenesis. Recent advances in our ability to perform global translatome analyses indicate that our understanding of translational changes in cancer resistance is still limited. Here, we characterize global translational changes that occur during the acquisition of prostate cancer (PCa) drug resistance. We generated a patient derived

    更新日期:2021-01-07
  • Agonistic CD40 antibody therapy induces tertiary lymphoid structures but impairs the response to immune checkpoint blockade in glioma
    bioRxiv. Cancer Biol. Pub Date : 2021-01-06
    Luuk van Hooren; Alessandra Vaccaro; Mohanraj Ramachandran; Konstantinos Vazaios; Sylwia Libard; Tiarne van de Walle; Maria Georganaki; Hua Huang; Ilkka Pietilä; Joey Lau; Maria H Ulvmar; Mikael CI Karlsson; Maria Zetterling; Sara M Mangsbo; Asgeir S Jakola; Thomas Olsson Bontell; Anja Smits; Magnus Essand; Anna Dimberg

    Gliomas are brain tumors characterized by immunosuppression. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors but are yet to be evaluated for glioma. Here, systemic delivery of αCD40 led to cytotoxic T cell dysfunction and impaired the response to immune checkpoint inhibitors in preclinical glioma models. This was associated with an accumulation of suppressive

    更新日期:2021-01-07
  • RASSF1C oncogene elicits amoeboid invasion, cancer stemness and invasive EVs via a novel SRC/Rho axis
    bioRxiv. Cancer Biol. Pub Date : 2021-01-06
    Maria Laura Tognoli; Nikola Vlahov; Sander Steenbeek; Anna M. Grawenda; Michael Eyres; David Cano-Rodriguez; Simon Scrace; Christiana Kartsonaki; Alex von Kriegsheim; Eduard Willms; Matthew Wood; Marianne G. Rots; Jacco van Rheenen; Eric O'Neill; Daniela Pankova

    Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here we show that the novel oncogene RASSF1C

    更新日期:2021-01-06
  • Low STING expression in a transplantable KrasG12D/P53ko lung cancer model contributes to SiglecF+ neutrophil and CD103+Treg accumulation in tumors
    bioRxiv. Cancer Biol. Pub Date : 2021-01-06
    Laurent Gros; Chiara Ursino; Julie Constanzo; Nadine Zangger; Etienne Meylan; Nathalie Bonnefoy; julien Faget

    Lung cancer is the leading cause of mortality by cancer worldwide. Non-small cell lung cancer is the most common type of lung cancer and mutations in the KRAS gene are frequently found in this pathology. While immune checkpoint inhibitors are providing new hope for lung cancer care, only a subset of patients show durable benefit from these new therapies designed to drive an efficient anti-tumor immune

    更新日期:2021-01-06
  • Extracellular matrix changes in colorectal carcinoma and correlation with lymph node metastasis
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Thérèse Rachell Theodoro; Rodrigo Lorenzetti Serrano; Karine Corcione Turke; Sarhan Sydney Saad; Marcelo Augusto Fontenelle Ribeiro Junior; Jaques Waisberg; Maria Aparecida Silva Pinhal

    The process of proliferation and invasion of tumor cells depends on changes in the extracellular matrix (ECM) through the activation of enzymes and alterations in the profile of ECM components. We aimed to investigate the mRNA and protein expression of ECM components such as heparanase (HPSE), heparanase-2 (HPSE2), matrix metalloproteinase-9 (MMP-9), and syndecan-1 (SYND1) in neoplastic and non-neoplastic

    更新日期:2021-01-06
  • The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Danny Legge; Li Ling; Whei Moriarty; David Lee; Marianna Szemes; Asef Zahed; Leonidas Panousopoulus; Wan Yun Chung; Yara Aghabi; Jasmin Barratt; Richard Williams; Kathy Pritchard-Jones; Karim Malik; Sebastian Oltean; Keith William Brown

    Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to

    更新日期:2021-01-06
  • Tumor-Antagonizing Fibroblasts Secrete Prolargin as Tumor Suppressor in Hepatocellular Carcinoma
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Barbara Chiavarina; Roberto Ronca; Yukihiro Otaka; Roger Bryan Sutton; Sara Rezzola; Takehiko Yokobori; Paola Chiodelli; Regis Souche; Antonio Maraver; Gavino Faa; Tetsunari Oyama; Stephanie Gofflot; Akeila Bellahcene; Olivier Detry; Philippe Delvenne; Vincent Castronovo; Masahiko Nishiyama; Andrei Turtoi

    Hepatocellular carcinoma (HCC) is a difficult to cure primary liver cancer. Recent breakthroughs in cancer treatment highlight the importance of the tumor microenvironment (TME) and its ability to promote or suppress tumor development. While understanding of this dual behaviour is expanding for immune cells, little is known for other stromal cells, and notably cancer-associated fibroblasts (CAF). Here

    更新日期:2021-01-06
  • Molecular analysis of prostate cancer: prostate tissue and urine proteomics based approach
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Amrita Mitra; Rajdeep Das; Surya Kant Choubey; Amit Mandal

    Benign prostatic hyperplasia (BPH) and prostate cancer are the most frequently diagnosed conditions in men above 60 years. BPH manifests as benign enlargement of the prostate gland causing pain and difficulty in micturition, often associated with other lower urinary tract symptoms. On the other hand, prostate cancer might initially set in as a tumor of no clinical significance, but can ultimately develop

    更新日期:2021-01-05
  • A Mechanistic Modeling Framework Reveals the Key Principles Underlying Tumor Metabolism
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Shubham Tripathi; Jun Hyoung Park; Shivanand Pudakalakatti; Pratip K. Bhattacharya; Benny Abraham Kaipparettu; Herbert Levine

    While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, utilizing glycolysis, oxidative phosphorylation, or both, and can switch between different metabolic phenotypes. A framework to analyze the observed metabolic heterogeneity

    更新日期:2021-01-05
  • HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Daniel J. García-Domínguez; Nabil Hajji; Sara Sanchez-Molina; Elisabet Figuerola; Rocío M. de Pablos; Ana M. Espinosa-Oliva; Eduardo Andrés-León; Laura Carmen Terrón-Camero; Rocío Flores-Campos; Guillem Pascual-Pasto; María José Robles; Angel M Carcaboso; Jaume Mora; Enrique de Alava; Lourdes Hontecillas-Prieto

    Ewing sarcoma (EWS) is an aggressive developmental sarcoma driven by a fusion gene, EWSR1-FLI1. However, little is known about the regulation of EWSR1-FLI1 chimeric fusion gene expression. Here, we demonstrate that active nuclear HDAC6 in EWS modulates acetylation status of specificity protein 1 (SP1), consequently regulating SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective

    更新日期:2021-01-05
  • Newcastle disease virus induced ferroptosis through p53-SLC7A11-GPX4 axis mediated nutrient deprivation in tumor cells
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Xianjin Kan; Yuncong Yin; Cuiping Song; Lei Tan; Xusheng Qiu; Ying Liao; Weiwei Liu; Songshu Meng; Yingjie Sun; Chan Ding

    A number of new cell death processes have been discovered in recent years, including ferroptosis, which is characterized by the accumulation of lipid peroxidation products derived from iron metabolism. The evidence suggests that ferroptosis has a tumor-suppressor function. However, the mechanism by which ferroptosis mediates the response of tumor cells to oncolytic viruses remains poorly understood

    更新日期:2021-01-05
  • Histone H3K4me3 and H3K9me3 are super over-methylated in soft tissue sarcoma compared to normal muscle in patient-derived xenograft (PDX) mouse models: an indicator of cancer methionine addiction
    bioRxiv. Cancer Biol. Pub Date : 2021-01-05
    Yusuke Aoki; Robert M. Hoffman; Kotaro Nishida; Itaru Endo; Michael Bouvet; Yoshihiko Tashiro; Sachiko Inubushi; Kazuyuki Hamada; Yasunori Tome; Jun Yamamoto

    Methionine addiction is a fundamental and general hallmark of cancer discovered by us almost a half-century ago [Proc Natl Acad Sci U S A 73 (1976) 1523-1527]. Methionine addiction is defined as the requirement, specific for cancer cells of all types, for exogenous methionine despite the normal ability to synthesize methionine from homocysteine. The methionine addiction of cancer is termed the Hoffman-effect

    更新日期:2021-01-05
  • Spatial Clustering of CD68+ Tumor Associated Macrophages with Tumor Cells is Associated with Worse Overall Survival in Metastatic Clear Cell Renal Cell Carcinoma
    bioRxiv. Cancer Biol. Pub Date : 2021-01-04
    Nicholas H Chakiryan; Gregory Kimmel; Youngchul Kim; Ali Hajiran; Ahmet Aydin; Logan Zemp; Esther Katende; Jonathan Nguyen; Neale Lopez-Blanco; Jad Chahoud; Philippe Spiess; Michelle Fournier; Jasrehman Dhillon; Liang Wang; Carlos Moran-Segura; Asmaa El-Kenawi; James Mule; Philipp M Altrock; Brandon J Manley

    Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular

    更新日期:2021-01-05
  • Phosphoproteomic Landscape of AML Cells Treated with the ATP-Competitive CK2 Inhibitor CX-4945
    bioRxiv. Cancer Biol. Pub Date : 2021-01-04
    Mauro Rosales; Arielis Rodriguez-Ulloa; Vladimir Besada; Ailyn C. Ramon; George V. Perez; Yassel Ramos; Osmany Guirola; Luis J. Gonzalez; Katharina Zettl; Jacek R. Wisniewski; Yasser Perera; Silvio E. Perea

    Casein kinase 2 (CK2) regulates a plethora of proteins with pivotal roles in solid and hematological neoplasia. Particularly, in acute myeloid leukemia (AML) CK2 has been pointed as an attractive therapeutic target and prognostic marker. Here, we explored the impact of CK2 inhibition over the phosphoproteome of two cell lines representing major AML subtypes. Quantitative phosphoproteomic analysis was

    更新日期:2021-01-05