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Lipid-laden macrophages recycle myelin to feed glioblastoma. Cancer Res. (IF 12.5) Pub Date : 2024-09-18 Lizhi Pang,Fei Zhou,Peiwen Chen
Tumor-associated microglia and macrophages (TAMs) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment (TME). Given the heterogeneity and plasticity of TAMs in the GBM TME, understanding the context-dependent cancer cell-TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell, Kloosterman
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A Paradigm Shift in Tumor Immunology: Th17 Cells and TGF-β in Intestinal Cancer Initiation Cancer Res. (IF 12.5) Pub Date : 2024-09-18 Megan M. Wyatt, Chrystal M. Paulos
Cancer remains one of the most complex challenges in modern medicine, with intricate relationships between immune responses and tumor development. This article examines a groundbreaking study by Fesneau, Thevin and colleagues, published in Nature Immunology. This elegant body of work explores the link between chronic inflammation and cancer, particularly focusing on Th17 cells involved in intestinal
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Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer Cancer Res. (IF 12.5) Pub Date : 2024-09-18 Chengying Cui, Haojie Zhang, Congcong Yang, Mingwei Yin, Xinkun Teng, Miaomiao Yang, Dejie Kong, Jinzhi Zhang, Weidong Peng, Zhimin Chu, Jingjing Wang, Yating Sun, Liping Kang, Bin Lyu, Qian Gao, Mingqing Wu, Yongqiang Wang, Yang Li
Currently, only 20-40% of cancer patients benefit from immune checkpoint inhibitors. Understanding the mechanisms underlying the immunosuppressive tumor microenvironment (TME) and characterizing dynamic changes in the immunological landscape during treatment are critical for improving responsiveness to immunotherapy. Here, we identified JNK signaling in cancer-associated fibroblasts (CAFs) as a regulator
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mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer Cancer Res. (IF 12.5) Pub Date : 2024-09-17 Kai Chen, Patrick Ernst, Anusua Sarkar, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D. Ringel, Xiaoguang Liu, Lufang Zhou
Mitochondria are important in various aspects of cancer development and progression. Targeting mitochondria in cancer cells holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we developed mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial
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CircRREB1 Mediates Metabolic Reprogramming and Stemness Maintenance to Facilitate Pancreatic Ductal Adenocarcinoma Progression Cancer Res. (IF 12.5) Pub Date : 2024-09-17 Zeyin Rong, Jin Xu, Jianhui Yang, Wei Wang, Rong Tang, Zifeng Zhang, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Chen Liang, Xianjun Yu, Si Shi
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumor with limited treatment options and poor patient survival. Circular RNAs (circRNAs) play crucial regulatory roles in the occurrence and development of various cancers, including PDAC. Here, using circRNA sequencing of diverse PDAC samples, we identified circRREB1 as an oncogenic circRNA that is significantly upregulated in PDAC and is
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Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer Cancer Res. (IF 12.5) Pub Date : 2024-09-17 Koki Oyama, Kohei Nakata, Chikanori Tsutsumi, Masataka Hayashi, Bo Zhang, Yuki Mochida, Tomohiko Shinkawa, Kento Hirotaka, Pingshan Zhong, Satomi Date, Haizhen Luo, Akihiro Kubo, Nobuhiro Higashijima, Yutaka Yamada, Toshiya Abe, Noboru Ideno, Kazuhiro Koikawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Hideya Onishi, Takashi Morisaki, Keiji Kuba, Yoshinao Oda, Masafumi Nakamura
The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, single-cell RNA-sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy
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Precise In Situ Delivery of a Photo-enhanceable Inflammasome-Activating Nanovaccine Activates Anti-cancer Immunity Cancer Res. (IF 12.5) Pub Date : 2024-09-17 Yang Zhou, Li Pang, Tao Ding, Kang Chen, Jinzhao Liu, Meicen Wu, Weiping Wang, Kwan Man
A variety of state-of-the-art nanovaccines (NVs) combined with immunotherapies have recently been developed to treat malignant tumors, showing promising results. However, immunosuppression in the tumor microenvironment (TME) restrains cytotoxic T cells infiltration and limits the efficacy of immunotherapies in solid tumors. Therefore, tactics for enhancing antigen cross-presentation and reshaping the
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CD24-Targeted NIR-II Fluorescence Imaging Enables Early Detection of Colorectal Neoplasia Cancer Res. (IF 12.5) Pub Date : 2024-09-17 Xiaoyong Guo, Shuangling Luo, Xiaofeng Wang, Yingying Cui, Miaomiao Li, Zeyu Zhang, Lidan Fu, Caiguang Cao, Xiaojing Shi, Haifeng Liu, Yawei Qu, Xiangyu Gao, Zhenhua Hu, Jie Tian
Colorectal cancer (CRC) continues to be a major health issue even though screening methods have facilitated early detection. Despite the high sensitivity of white-light colonoscopy, it frequently overlooks invasive flat or depressed lesions, which can lead to the development of larger, advanced tumors. Fluorescence molecular imaging (FMI) offers a promising approach for early tumor detection by targeting
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The Pivotal Role of Germline BRCA2 Pathogenic Variants in “Apparently Sporadic” Pancreatic Cancer Cancer Res. (IF 12.5) Pub Date : 2024-09-16 Jonathan R. Brody, Alison P. Klein
In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of
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Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells Cancer Res. (IF 12.5) Pub Date : 2024-09-12 Xiaoyu Liu, Yu Liu, Qing Rao, Yihan Mei, Haiyan Xing, Runxia Gu, Junli Mou, Manling Chen, Fan Ding, Wanqing Xie, Kejing Tang, Zheng Tian, Min Wang, Shaowei Qiu, Jianxiang Wang
Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSCs) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of pre-leukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1-ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded
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Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling Cancer Res. (IF 12.5) Pub Date : 2024-09-12 Ming Luo, Na Shen, Li Shang, Zeng Fang, Ying Xin, Yuxi Ma, Min Du, Yuan Yuan, Chenchen Hu, Yun Tang, Jing Huang, Wei Wei, Myung Ryul Lee, Paul J. Hergenrother, Max S. Wicha
Triple negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSCs), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets including NQO1. Here, we identified the antioxidant enzymes NQO1 and SOD1
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Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1 Cancer Res. (IF 12.5) Pub Date : 2024-09-12 Kathia E. Rodarte, Shaked Nir Heyman, Lei Guo, Lydia Flores, Trisha K. Savage, Juan Villarreal, Su Deng, Lin Xu, Rajal B. Shah, Trudy G. Oliver, Jane E. Johnson
Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-independent neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the progression to NEPC suggests a model of lineage plasticity whereby AR-dependent
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Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer Cancer Res. (IF 12.5) Pub Date : 2024-09-09 Huijuan Wang, Jiaxin Chen, Xiaoyu Chen, Yingqiang Liu, Jiawei Wang, Qing Meng, Huogang Wang, Ying He, Yujia Song, Jingyun Li, Zhenyu Ju, Peng Xiao, Junbin Qian, Zhangfa Song
Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma. Identifying the key molecular determinants for the pro-tumor properties of CAFs could enable the development of more effective treatment strategies. Herein, through analyses of single-cell sequencing data, we identified a population of CAFs
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Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-type Non-Small Cell Lung Cancer Cancer Res. (IF 12.5) Pub Date : 2024-09-09 Margaret R. Smith, Caroline B. Dixon, Yuezhu Wang, Yin Liu, Ralph D’Agostino, Jimmy Ruiz, George Oliver, Lance D. Miller, Umit Topaloglu, Michael D. Chan, Michael Farris, Jing Su, Kathryn F. Mileham, Dawen Zhao, Wencheng Li, Tammy Sexton, Thomas Lycan, Karen M. Haas, Jason M. Grayson, Fei Xing
Treatment of non-small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anti-cancer effects of immune-checkpoint inhibitors (ICI). However, only 20% of NSCLC patients benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 NSCLC patients who received ICI treatments
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MYC Drives mRNA Pseudouridylation to Mitigate Proliferation-Induced Cellular Stress during Cancer Development Cancer Res. (IF 12.5) Pub Date : 2024-09-06 Jane Ding, Mohit Bansal, Yuxia Cao, Bingwei Ye, Rui Mao, Anamika Gupta, Sunil Sudarshan, Han-Fei Ding
Pseudouridylation is a common RNA modification that is catalyzed by the family of pseudouridine synthases (PUS). Pseudouridylation can increase RNA stability and rigidity, thereby impacting RNA splicing, processing, and translation. Given that RNA metabolism is frequently altered in cancer, pseudouridylation may be a functionally important process in tumor biology. Here, we showed that the MYC family
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The Pan-tumor Vasculature Under the Transcriptomic Magnifying Glass Cancer Res. (IF 12.5) Pub Date : 2024-09-06 Krish Skandha Gopalan, Gabriele Bergers
In the first pan-cancer analysis of the tumor vasculature, Pan and colleagues profile nearly 200,000 endothelial and mural cells (ECs and MCs), identifying novel subclusters and cell states using consensus trajectory inference. They identify differentiation trajectories in vascular and lymphatic endothelial cells, and subtype the pericyte population. During sprouting angiogenesis, venous cells dedifferentiate
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B7-H3-Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity Against Solid Tumors Cancer Res. (IF 12.5) Pub Date : 2024-09-06 Licui Jiang, Fengtao You, Hai Wu, Changsong Qi, Shufen Xiang, Ping Zhang, Huimin Meng, Min Wang, Jiequn Huang, Yafen Li, Dan Chen, Gangli An, Nan Yang, Bozhen Zhang, Lin Shen, Lin Yang
Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen-presentation pathway, making them a potential “off-the-shelf” cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale
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ARID1A-Deficient Tumors Acquire Immunogenic Neoantigens during the Development of Resistance to Targeted Therapy Cancer Res. (IF 12.5) Pub Date : 2024-09-04 Masahiro Okada, Satoru Yamasaki, Hiroshi Nakazato, Yuhya Hirahara, Takuya Ishibashi, Masami Kawamura, Kanako Shimizu, Shin-ichiro Fujii
Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions
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Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis. Cancer Res. (IF 12.5) Pub Date : 2024-09-04 Yinyin Shu,Xiaoni Jin,Mintao Ji,Zhisen Zhang,Xiuxiu Wang,Haisheng Liang,Shuangshuang Lu,Shuai Dong,Yiping Lin,Yuhan Guo,Qiuyu Zhuang,Yuhong Wang,Zhe Lei,Lingchuan Guo,Xuanyu Meng,Guangming Zhou,Wensheng Zhang,Lei Chang
Yes-associated protein (YAP) is a central player in cancer development, with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/transcriptional coactivator with PDZ-binding motif (TAZ) and the DNA damage response. Here, we investigated the mechanistic underpinnings of the cross-talk between DNA damage repair and YAP activity. Ku70
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Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression. Cancer Res. (IF 12.5) Pub Date : 2024-09-04 Lingling Li,Dongxian Jiang,Hui Liu,Chunmei Guo,Qiao Zhang,Xuedong Li,Xiaojian Chen,Zheqi Chen,Jinwen Feng,Subei Tan,Wen Huang,Jie Huang,Chen Xu,Chen-Ying Liu,Wei Yu,Yingyong Hou,Chen Ding
Colorectal cancer is the second most common malignant tumor worldwide. Analysis of the changes that occur during colorectal cancer progression could provide insights into the molecular mechanisms driving colorectal cancer development and identify improved treatment strategies. In this study, we performed an integrated multiomic analysis of 435 trace tumor samples from 148 patients with colorectal cancer
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Extracellular Vesicle-Packaged ACSL4 Induces Hepatocyte Senescence to Promote Hepatocellular Carcinoma Progression Cancer Res. (IF 12.5) Pub Date : 2024-09-03 Pei-pei Hou, Chong-ming Zheng, Si-hong Wu, Xi-xiao Liu, Guang-xin Xiang, Wei-yang Cai, Gang Chen, Yong-liang Lou
Extracellular vesicles (EVs) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase
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Neural Circuitries between the Brain and Peripheral Solid Tumors Cancer Res. (IF 12.5) Pub Date : 2024-09-03 Xiang Chen, Yuli Geng, Guanxin Wei, Danzeng He, Jialong Lv, Wenhao Wen, Fan Xiang, Kaixiong Tao, Chuanqing Wu
The recent discovery of the pivotal role of central nervous system (CNS) in controlling tumor initiation and progression has opened a new field of research. Increasing evidence suggests a bidirectional interaction between the brain and tumors. The brain influences the biological behavior of tumor cells through complex neural networks involving the peripheral nervous system, the endocrine system, and
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Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1-Mutant Lung Cancer Cancer Res. (IF 12.5) Pub Date : 2024-08-29 Junghui Koo, Chang-Soo Seong, Rebecca E. Parker, Amy Herrera, Bhakti Dwivedi, Robert A. Arthur, Ashok Reddy. Dinasarapu, H. Richard. Johnston, Henry Claussen, Carol Tucker-Burden, Suresh S. Ramalingam, Haian Fu, Wei Zhou, Adam I. Marcus, Melissa Gilbert-Ross
The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical strategies designed to exploit growth within the context of invasion are lacking. To address this, we designed an experimental
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Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment Cancer Res. (IF 12.5) Pub Date : 2024-08-29 Chanju Lee, Dahee Yu, Hyung-Seok Kim, Ki Sun Kim, Chi Young Chang, Hee Jung Yoon, Su Bin Won, Dae Yeon Kim, Eun Ah Goh, Yong Sun Lee, Jong Bae Park, Sang Soo Kim, Eun Jung Park
Galectin-9 is a multifaceted regulator of various pathophysiological processes that exerts positive or negative effects in a context-dependent manner. Here, we elucidated the distinctive functional properties of galectin-9 on myeloid cells within the brain tumor microenvironment. Galectin-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared
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Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Mi Li, Amriti R. Lulla, Yan Wang, Spyros Tsavachidis, Fuchenchu Wang, Cansu Karakas, Tuyen D.T. Nguyen, Tuyen N. Bui, Marc A. Pina, Mei-Kuang Chen, Sofia Mastoraki, Asha S. Multani, Natalie W. Fowlkes, Aysegul Sahin, C. Gary. Marshall, Kelly K. Hunt, Khandan Keyomarsi
Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. Cleavage of full-length cyclin E (FL-cycE) to low molecular weight isoforms (LMW-E) dramatically alters the substrate specificity, promoting G1/S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1
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A Dual-Payload Antibody-Drug Conjugate Targeting CD276/B7-H3 Elicits Cytotoxicity and Immune Activation in Triple-Negative Breast Cancer Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Zhuoxin Zhou, Yingnan Si, Jiashuai Zhang, Kai Chen, Ashley George, Seulhee Kim, Lufang Zhou, XXiaoguang Liu
Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous disease that often relapses following treatment with standard radiotherapies and cytotoxic chemotherapies. Combination therapies have potential for treating refractory metastatic TNBC. Here, we aimed to develop an antibody-drug conjugate with dual payloads (DualADC) as a chemo-immunotherapy for TNBC. The overexpression of
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Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Graham MacLeod, Fatemeh Molaei, Shahan Haider, Maira P. Almeida, Sichun Lin, Michelle Kushida, Haresh Sureshkumar, Jasmine K. Bhatti, Jack Q. Lu, Daniel Schramek, Peter B. Dirks, Stephane Angers
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults and is driven by self-renewing glioblastoma stem cells (GSCs) that persist after therapy and seed treatment refractory recurrent tumors. GBM tumors display a high degree of intra- and inter-tumoral heterogeneity that is a prominent barrier to targeted treatment strategies. This heterogeneity extends to GSCs that exist on
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Targeting Galectin-1 Overcomes Paclitaxel Resistance in Esophageal Squamous Cell Carcinoma Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Liting Zhou, Jie Tian, Keke Wang, Yijie Ma, Xiaojie Chen, Hui Luo, Bingbing Lu, Nan Wang, Penglei Wang, Xuejiao Liu, Ran Zhao, Simin Zhao, Jiutao Wang, Wenna Nie, Hong Ge, Wenting Liu, Tingxuan Gu, Kangdong Liu, Mee-Hyun Lee, Xiang Li, Zigang Dong
Resistance to paclitaxel poses a major obstacle in esophageal squamous cell carcinoma (ESCC) treatment. A better understanding of the mechanisms underlying paclitaxel resistance could help identify prognostic biomarkers and improved therapeutic strategies. In this study, we established a patient-derived xenograft (PDX) model of acquired paclitaxel resistance and used RNA-sequencing to identify galectin-1
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Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Yu-Wei Li, Lei-Jie Dai, Xiang-Rong Wu, Shen Zhao, Yu-Zheng Xu, Xi Jin, Yi Xiao, Ying Wang, Cai-Jin Lin, Yi-Fan Zhou, Tong Fu, Wen-Tao Yang, Ming Li, Hong Lv, Siyuan Chen, Anita Grigoriadis, Yi-Zhou Jiang, Ding Ma, Zhi-Ming Shao
HER2-positive breast cancer is an aggressive subtype that accounts for 15-20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. Here, we performed
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Bottom-up or Top-down: Inflammation Reprograms Paneth Cells to Develop Bowel Cancers Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Julian Chua, Alex Gregorieff, Arshad Ayyaz
The origins of colorectal cancer (CRC) have long been a subject of intense debate. Early observations noted cancer formation in the human gut slightly above the base of crypts, the structural and functional units of the regenerative compartment of the intestinal epithelium. This suggested that the cells of origin for CRC reside close to the crypt-villus junction, where more differentiated cells are
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Tumour’s Digest: Macrophage metabolism creates a barrier to T cells Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Eleanor Jane. Tyler, Oliver M.T. Pearce
Changes in the composition and physical properties of the tumor extracellular matrix are linked to poor cytotoxic T-cell infiltration and therapy response, yet the underlying mechanisms remain unclear. Tharp and colleagues revealed a fascinating cascade where tumor fibrosis alters macrophage metabolism, restricting the nutrients available to infiltrating T-cells and resulting in their suppression and
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CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Michael W. Lewis, Caitlin M. King, Kamila Wisniewska, Matthew J. Regner, Alisha Coffey, Michael R. Kelly, Raul Mendez-Giraldez, Eric S. Davis, Douglas H. Phanstiel, Hector L. Franco
Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer, which is due in part to the paucity of targeted therapies. A systematic analysis of regulatory elements that extend beyond protein coding genes could uncover avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with
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PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma Cancer Res. (IF 12.5) Pub Date : 2024-08-26 Sarah Spear, Olivia Le Saux, Hasan B. Mirza, Nayana Iyer, Katie Tyson, Fabio Grundland Freile, Josephine B. Walton, Chloe Woodman, Sheba Jarvis, Darren P. Ennis, Carmen Aguirre Hernandez, Yuewei Xu, Pavlina Spiliopoulou, James D. Brenton, Ana P. Costa-Pereira, David P. Cook, Barbara C. Vanderhyden, Hector C. Keun, Evangelos Triantafyllou, James N. Arnold, Iain A. McNeish
High-grade serous ovarian carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity
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Hypoxia Stimulates PYGB Enzymatic Activity to Promote Glycogen Metabolism and Cholangiocarcinoma Progression. Cancer Res. (IF 12.5) Pub Date : 2024-08-20 Yani Pan,Yue Zhou,Yonghua Shen,Lei Xu,Hongwen Liu,Nannan Zhang,Tianlu Huang,Kui Meng,Yu Liu,Lishan Wang,Ge Bai,Qi Chen,Yun Zhu,Xiaoping Zou,Siliang Wang,Zhangding Wang,Lei Wang
Cholangiocarcinoma (CCA) displays enhanced glycolysis, pivotal for fulfilling the heightened energy demands intrinsic to its malignant progression. Recent research has indicated that endogenous glycogen rather than exogenous glucose acts as the major carbon source for glycolysis, highlighting the need to better understand the regulation of glycogen homeostasis in CCA. Here, through comprehensive integrative
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NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma Cancer Res. (IF 12.5) Pub Date : 2024-08-19 Wei Lin, Na Wang, Shihao Wu, Mingxin Diao, Quanfu Huang, Kuo Li, Peiyuan Mei, Xiaojun Wang, Yongde Liao, Yunchong Meng
Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in advanced non-small cell lung carcinoma (NSCLC) patients with EGFR-activating mutations or the T790M resistance mutation. However, the efficacy of osimertinib is limited due to acquired resistance, highlighting the need to elucidate resistance mechanisms to facilitate the
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Serine Depletion Promotes Antitumor Immunity by Activating Mitochondrial DNA-Mediated cGAS-STING Signaling. Cancer Res. (IF 12.5) Pub Date : 2024-08-15 Suchandrima Saha,Monisankar Ghosh,Jinyu Li,Asher Wen,Lorenzo Galluzzi,Luis A Martinez,David C Montrose
Serine is critical for supporting cancer metabolism, and depriving malignant cells of this nonessential amino acid exerts antineoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. In this study, we demonstrated
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CDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer. Cancer Res. (IF 12.5) Pub Date : 2024-08-15 Wei Li,Feng Guo,Ruijiang Zeng,Huaiyuan Liang,Yinhuai Wang,Wei Xiong,Heshui Wu,Chunguang Yang,Xin Jin
The efficacy of immunotherapy in patients with prostate cancer is limited due to the "cold" tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis is involved in innate immunity and has been increasingly recognized as a candidate target for cancer immunotherapy. Here, we found that treatment with CDK4/6 inhibitors stimulates the STING pathway and enhances the antitumor
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Integration of Clinical Trial Spatial Multiomics Analysis and Virtual Clinical Trials Enables Immunotherapy Response Prediction and Biomarker Discovery. Cancer Res. (IF 12.5) Pub Date : 2024-08-15 Shuming Zhang,Atul Deshpande,Babita K Verma,Hanwen Wang,Haoyang Mi,Long Yuan,Won Jin Ho,Elizabeth M Jaffee,Qingfeng Zhu,Robert A Anders,Mark Yarchoan,Luciane T Kagohara,Elana J Fertig,Aleksander S Popel
Due to the lack of treatment options, there remains a need to advance new therapeutics in hepatocellular carcinoma (HCC). The traditional approach moves from initial molecular discovery through animal models to human trials to advance novel systemic therapies that improve treatment outcomes for patients with cancer. Computational methods that simulate tumors mathematically to describe cellular and
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Increased Protein Kinase A Activity Induces Fibrolamellar Hepatocellular Carcinoma Features Independent of DNAJB1. Cancer Res. (IF 12.5) Pub Date : 2024-08-15 Mahsa Shirani,Solomon Levin,Bassem Shebl,David Requena,Tova M Finkelstein,Daniel S Johnson,Denise Ng,Gadi Lalazar,Søren Heissel,Peter Hojrup,Henrik Molina,Ype P de Jong,Charles M Rice,Aatur D Singhi,Michael S Torbenson,Philip Coffino,Barbara Lyons,Sanford M Simon
Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that is driven by the fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA activity is controlled through regulatory proteins that both inhibit catalytic activity and control localization, and an excess of regulatory subunits ensures PRKACA activity is inhibited. Here, we found an increase in the ratio
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Transient Differentiation-State Plasticity Occurs during Acute Lymphoblastic Leukemia Initiation. Cancer Res. (IF 12.5) Pub Date : 2024-08-15 Vera M Poort,Rico Hagelaar,Markus J van Roosmalen,Laurianne Trabut,Jessica G C A M Buijs-Gladdines,Bram van Wijk,Jules Meijerink,Ruben van Boxtel
Leukemia is characterized by oncogenic lesions that result in a block of differentiation, whereas phenotypic plasticity is retained. A better understanding of how these two phenomena arise during leukemogenesis in humans could help inform diagnosis and treatment strategies. Here, we leveraged the well-defined differentiation states during T-cell development to pinpoint the initiation of T-cell acute
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CENP-E Inhibition Induces Chromosomal Instability and Synergizes with Diverse Microtubule-Targeting Agents in Breast Cancer. Cancer Res. (IF 12.5) Pub Date : 2024-08-15 John B Tucker,Caleb L Carlsen,Christina M Scribano,Srishrika M Pattaswamy,Mark E Burkard,Beth A Weaver
Drugs that perturb microtubules are commonly used to treat breast cancers of all subtypes in both early stage and metastatic disease, but they are effective in only approximately 50% of patients. High concentrations of microtubule-targeting agents can elicit mitotic arrest in cell culture models; however, recent evidence from primary and metastatic breast cancers has revealed that these agents only
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An Immunometabolic Route for Activating cGAS/STING to Drive Anticancer Immunity Cancer Res. (IF 12.5) Pub Date : 2024-08-15 Francisca Borges, Abhishek D. Garg
The cGAS/STING pathway is a crucial immune activator in cancer biology, triggering innate immunosurveillance against tumors by sensing and reacting to endogenous mitochondrial DNA (mtDNA). In this issue of Cancer Research, research by Saha and colleagues highlights the significant impact of serine deprivation on this pathway, thereby unveiling its potential for anticancer therapy. Serine is essential
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YAP1 Inhibition Induces Phenotype Switching of Cancer-Associated Fibroblasts to Tumor Suppressive in Prostate Cancer Cancer Res. (IF 12.5) Pub Date : 2024-08-13 Hongtao Song, Tong Lu, Donghui Han, Jiayu Zhang, Lunbiao Gan, Chao Xu, Shaojie Liu, Peng Li, Keying Zhang, Zhihao Hu, Hongji Li, Yu Li, Xiaolong Zhao, Jingliang Zhang, Nianzeng Xing, Changhong Shi, Weihong Wen, Fa Yang, Weijun Qin
Prostate cancer (PCa) rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAFs) are critical components of the immunologically “cold” tumor microenvironment and are considered a promising target to enhance the immunotherapy response. In this study, we aimed to reveal the mechanisms regulating CAF plasticity to identify potential strategies to switch CAFs from
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The Neurodevelopmental Protein POGZ Suppresses Metastasis in Triple Negative Breast Cancer by Attenuating TGFβ Signaling Cancer Res. (IF 12.5) Pub Date : 2024-08-13 John Heath, Caitlynn Mirabelli, Matthew G. Annis, Valerie Sabourin, Steven Hébert, Steven Findlay, HaEun Kim, Michael Witcher, Claudia L. Kleinman, Peter M. Siegel, Alexandre Orthwein, Josie Ursini-Siegel
The pogo transposable element derived zinc finger protein, POGZ, is notably associated with neurodevelopmental disorders through its role in gene transcription. Many proteins involved in neurological development are often dysregulated in cancer, suggesting a potential role for POGZ in tumor biology. Here, we provided experimental evidence that POGZ influences the growth and metastatic spread of triple
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H3K18 Lactylation Potentiates Immune Escape of Non-Small Cell Lung Cancer Cancer Res. (IF 12.5) Pub Date : 2024-08-13 Cai Zhang, Lijie Zhou, Mingyuan Zhang, Yue Du, Cai Li, Huijun Ren, Lu Zheng
The recently discovered epigenetic modification lysine lactylation (Kla) contributes to tumor development and progression in several types of cancer. In addition to the tumor-intrinsic effects, histone lactylation may mediate tumor microenvironment remodeling and immune evasion. Here, we observed elevated pan Kla and H3K18la levels in non-small cell lung cancer (NSCLC) tissues, which was positively
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LTβR Agonism Promotes Anti-Tumor Immune Responses via Modulation of the Tumor Microenvironment Cancer Res. (IF 12.5) Pub Date : 2024-08-13 Disi An, Guoying Chen, Wei-Yi Cheng, Katja Mohrs, Christina Adler, Namita T. Gupta, Gurinder S. Atwal, David J. DiLillo, Christopher Daly, John C. Lin, Frank Kuhnert
The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune-checkpoint blockade (ICB) in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses may facilitate development of improved treatment
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Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer Cancer Res. (IF 12.5) Pub Date : 2024-08-13 Jeffrey H. Becker, Anastasia E. Metropulos, Christina Spaulding, Alejandra M. Marinelarena, Mario A. Shields, Daniel R. Principe, Thao D. Pham, Hidayatullah G. Munshi
MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the pro-apoptotic protein BIM in PDAC cells and conferred sensitivity
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DAZAP1 Phase Separation Regulates Mitochondrial Metabolism to Facilitate Invasion and Metastasis of Oral Squamous Cell Carcinoma Cancer Res. (IF 12.5) Pub Date : 2024-08-09 Jiayi Zhang, Zihui Ni, Yu Zhang, Yan Guo, Rundong Zhai, Mengqi Wang, Zizhen Gong, Mengyao Wang, Fanrui Zeng, Ziyue Gu, Qianming Chen, Laikui Liu, Zhiyong Wang, Weiwen Zhu
Tumor invasion and metastasis are the underlying causes of the high mortality rate of oral squamous cell carcinoma (OSCC). Energy metabolism reprogramming has been identified as a crucial process mediating tumor metastasis, thus indicating an urgent need for in-depth investigation of the specific mechanisms of tumor energy metabolism. Here, we identified an RNA-binding protein, DAZ associated protein
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Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication Cancer Res. (IF 12.5) Pub Date : 2024-08-09 Jayaprakash Mandal, Tiffany Nicole. Jones, Juliane Marie. Liberto, Stephanie Gaillard, Tian-Li Wang, Ie-Ming Shih
Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and epidermal growth factor receptor (EGFR), which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both
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KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression Cancer Res. (IF 12.5) Pub Date : 2024-08-09 Zilan Xu, Yifan Zhou, Shaoqiu Liu, Hongzhe Zhao, Ziming Chen, Rui Li, Mei Li, Xudong Huang, Shuang Deng, Lingxing Zeng, Sihan Zhao, Shaoping Zhang, Xiaowei He, Ji Liu, Chunling Xue, Ruihong Bai, Lisha Zhuang, Quanbo Zhou, Rufu Chen, Dongxin Lin, Jian Zheng, Jialiang Zhang
N6-methyladenosine (m6A) is the most prevalent RNA modification and is associated with various biological processes. Proteins that function as readers and writers of m6A modifications have been shown to play critical roles in human malignancies. Here, we identified KH-type splicing regulatory protein (KHSRP) as an m6A binding protein that contributes to the progression of pancreatic ductal adenocarcinoma
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A Genomics-Driven Artificial Intelligence-Based Model Classifies Breast Invasive Lobular Carcinoma and Discovers CDH1 Inactivating Mechanisms Cancer Res. (IF 12.5) Pub Date : 2024-08-06 Fresia Pareja, Higinio Dopeso, Yi Kan Wang, Andrea M. Gazzo, David N. Brown, Monami Banerjee, Pier Selenica, Jan H. Bernhard, Fatemeh Derakhshan, Edaise M. da Silva, Lorraine Colon-Cartagena, Thais Basili, Antonio Marra, Jillian Sue, Qiqi Ye, Arnaud Da Cruz Paula, Selma Yeni Yildirim, Xin Pei, Anton Safonov, Hunter Green, Kaitlyn Y. Gill, Yingjie Zhu, Matthew C.H. Lee, Ran A. Godrich, Adam Casson,
Artificial intelligence (AI)-systems can improve cancer diagnosis, yet their development often relies on subjective histological features as ground truth for training. Here, we developed an AI-model applied to histological whole-slide images (WSIs) using CDH1 bi-allelic mutations, pathognomonic for invasive lobular carcinoma (ILC) in breast neoplasms, as ground truth. The model accurately predicted
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Induced Pluripotent Stem Cells Facilitate the Development and Evaluation of Cancer Vaccines Cancer Res. (IF 12.5) Pub Date : 2024-08-06 Yuewen Zhai, Xinyu Xu, Ji Fang, Fang He, Siwen Li
Cancer vaccines are an approach to elicit amplified antigen-specific immune responses. Induced pluripotent stem cells (iPSCs) have potential utility for the development of universal vaccines due to their intrinsic antigenic epitopes. Concurrently, iPSCs can undergo pluripotent differentiation and are thus a stable source of both antigen-presenting cells for producing immune cell-based vaccines and
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Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy Cancer Res. (IF 12.5) Pub Date : 2024-08-06 Grace G. Bushnell, Deeksha Sharma, Henry C. Wilmot, Michelle Zheng, Toluwaleke D. Fashina, Chloe M. Hutchens, Samuel Osipov, Monika Burness, Max S. Wicha
Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cancer cells display “stem like” properties (CSCs), which may be regulated by
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An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia Cancer Res. (IF 12.5) Pub Date : 2024-08-02 Manuel Torres-Diz, Clara Reglero, Catherine D. Falkenstein, Annette Castro, Katharina E. Hayer, Caleb M. Radens, Mathieu Quesnel-Vallières, Zhiwei Ang, Priyanka Sehgal, Marilyn M. Li, Yoseph Barash, Sarah K. Tasian, Adolfo Ferrando, Andrei Thomas-Tikhonenko
Relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) is a major cause of pediatric cancer-related deaths. Relapse-specific mutations do not account for all chemotherapy failures in B-ALL patients, suggesting additional mechanisms of resistance. By mining RNA-seq datasets of paired diagnostic/relapse pediatric B-ALL samples, we discovered pervasive alternative splicing (AS) patterns linked
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LX1 Targets Androgen Receptor Variants and AKR1C3 to overcome Therapy Resistance in Advanced Prostate Cancer Cancer Res. (IF 12.5) Pub Date : 2024-08-02 Shu Ning, Cameron M. Armstrong, Enming Xing, Amy R. Leslie, Richard Y. Gao, Masuda Sharifi, Zachary A. Schaaf, Wei Lou, Xiangrui Han, Desiree H. Xu, Rui Yang, Jeffrey Cheng, Shabber Mohammed, Nicholas Mitsiades, Chengfei Liu, Alan P. Lombard, Chun-Yi Wu, Xiolin Cheng, Pui-Kai Li, Allen C. Gao
The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for therapeutic strategies targeting key resistance drivers, such as AR variants like AR-V7 and steroidogenic enzymes like AKR1C3, to improve outcomes for patients with advanced prostate
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Integrative Modeling of Signaling Network Dynamics Identifies Cell Type-selective Therapeutic Strategies for FGFR4-driven Cancers Cancer Res. (IF 12.5) Pub Date : 2024-08-02 Sungyoung Shin, Nicole J. Chew, Milad Ghomlaghi, Anderly C. Chüeh, Yunhui Jeong, Lan K. Nguyen, Roger J. Daly
Oncogenic FGFR4 signaling represents a potential therapeutic target in various cancer types, including triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC). However, resistance to FGFR4 single-agent therapy remains a major challenge, emphasizing the need for effective combinatorial treatments. Our study sought to develop a comprehensive computational model of FGFR4 signaling and
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Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma Cancer Res. (IF 12.5) Pub Date : 2024-08-02 Meng Jiao, Christopher J. Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R. Saban, Fang Li, Chuan-Yuan Li
Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of currently approved drugs known to cross the blood-brain barrier can facilitate rapid
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HTS384 NCI60: The Next Phase of the NCI60 Screen. Cancer Res. (IF 12.5) Pub Date : 2024-08-01 Mark W Kunkel,Nathan P Coussens,Joel Morris,Ronald C Taylor,Thomas S Dexheimer,Eric M Jones,James H Doroshow,Beverly A Teicher
The NCI60 human tumor cell line screen has been in operation as a service to the cancer research community for more than 30 years. The screen operated with 96-well plates, a 2-day exposure period to test agents, and following cell fixation, a visible absorbance endpoint by the protein-staining dye sulforhodamine B. In this study, we describe the next phase of this important cancer research tool, the
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Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers. Cancer Res. (IF 12.5) Pub Date : 2024-08-01 Patricia J Keller,Elizabeth J Adams,Rentian Wu,Alexandre Côté,Shilpi Arora,Nico Cantone,Rosana Meyer,Jennifer A Mertz,Victor Gehling,Jike Cui,Jacob I Stuckey,Avinash Khanna,Feng Zhao,Zehua Chen,Ziyang Yu,Richard T Cummings,Mohammed Taimi,Nehal J Lakhani,Drew Rasco,Martin Gutierrez,Linda Duska,Michael Devitt,Ronda Rippley,Julian Levell,Jennifer Truong,Jing Wang,Kaiming Sun,Patrick Trojer
Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations
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Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer. Cancer Res. (IF 12.5) Pub Date : 2024-08-01 Xiaohui Sun,Shiv P Verma,Guochong Jia,Xinjun Wang,Jie Ping,Xingyi Guo,Xiao-Ou Shu,Jianhong Chen,Andriy Derkach,Qiuyin Cai,Xiaolin Liang,Jirong Long,Kenneth Offit,Jung H Oh,Anne S Reiner,Gordon P Watt,Meghan Woods,Yaohua Yang,Christine B Ambrosone,Stefan Ambs,Yu Chen,Patrick Concannon,Montserrat Garcia-Closas,Jian Gu,Christopher A Haiman,Jennifer J Hu,Dezheng Huo,Esther M John,Julia A Knight,Christopher
Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying