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Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer Cancer Res. (IF 12.5) Pub Date : 2024-07-18 Alissandra L. Hillis, Timothy D. Martin, Haley E. Manchester, Jenny Högström, Na Zhang, Emmalyn Lecky, Nina Kozlova, Jonah Lee, Nicole S. Persky, David E. Root, Myles Brown, Karen Cichowski, Stephen J. Elledge, Taru Muranen, David A. Fruman, Simon T. Barry, John G. Clohessy, Ralitsa R. Madsen, Alex Toker
Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors
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NAT10 Phase Separation Regulates YTHDF1 Splicing to Promote Gastric Cancer Progression Cancer Res. (IF 12.5) Pub Date : 2024-07-18 Songyi Liu, Chunlin Lin, Xiang Lin, Penghang Lin, Ruofan He, Xiaoyu Pan, Yan Lin, Jianxin Ye, Guangwei Zhu
Gastric cancer (GC) is an aggressive malignancy with poor patient outcomes. NAT10 is an acetyltransferase that has been reported to contribute to GC progression. In-depth investigation into the underlying molecular mechanisms driven by NAT10 could help identify therapeutic targets to improve GC treatment. Here, we found that NAT10 forms condensates to regulate RNA dynamics and promote GC progression
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Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia Cancer Res. (IF 12.5) Pub Date : 2024-07-18 Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V. Dharia, Ashleigh Meyer, Lucy A. Merickel, Delan Khalid, Sebastian Scheich, Bjorn Haupl, Louis M. Staudt, Thomas Oellerich, Kimberly Stegmaier
Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships
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CCN6 suppresses metaplastic breast carcinoma by antagonizing WNT/β-catenin signaling to inhibit EZH2-driven EMT Cancer Res. (IF 12.5) Pub Date : 2024-07-18 Maria E. Gonzalez, Bryce Brophy, Ahmad Eido, Adele E. Leonetti, Sabra I. Djomehri, Giuseppina Augimeri, Nicholas J. Carruthers, Raymond G. Cavalcante, Francesca Giordano, Sebastiano Andò, Alexey I. Nesvizhskii, Eric R. Fearon, Celina G. Kleer
Metaplastic breast carcinomas (mBrCAs) are a highly aggressive subtype of triple negative breast cancer (TNBC) with histological evidence of epithelial to mesenchymal transition (EMT) and aberrant differentiation. Inactivation of the tumor suppressor gene CCN6 (also known as WISP3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle
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Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer Cancer Res. (IF 12.5) Pub Date : 2024-07-18 Jianqiang Yang, Fanghui Chen, Liwei Lang, Fan Yang, Zhenzhen Fu, Juan Martínez, Amber Cho, Nabil F. Saba, Yong Teng
Head and neck squamous cell carcinoma (HNSCC) is addicted to glutaminolysis. Targeting this metabolic dependency has emerged as a potential therapeutic approach for HNSCC. Here, we conducted a bioinformatic analysis of the TCGA HNSCC cohort that revealed a robust correlation between expression of c-Myc and GLS1, which catalyzes the first step in glutaminolysis. Intriguingly, disruption of GLS1 signaling
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Is There a Mathematician on Board? Cancer Res. (IF 12.5) Pub Date : 2024-07-15 Elana J. Fertig
As convergence science is emerging as a theme in cancer research, scientists from diverse backgrounds, including mathematics, are increasingly entering our research community. The captain of a Southwest Airlines flight recently paged in jest for a mathematician to help support fuel calculations that would enable a flight to arrive safely at the American Association for Cancer Research (AACR) Annual
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Earliest Metabolic Changes Associated with the Initiation of Pancreatic Cancer Cancer Res. (IF 12.5) Pub Date : 2024-07-15 Peter Storz
Pancreatic cancer is usually detected at a late stage, when tumors have already metastasized; therefore, it has a poor prognosis with a 5-year survival rate of 11% to 12%. A key to targeting this high mortality is to develop methods for detecting the disease at a stage in which it is still local to the pancreas. However, this needs a better understanding of the events that govern pancreatic cancer
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Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to-Ductal Metaplasia Cancer Res. (IF 12.5) Pub Date : 2024-07-15 Thorsten Neuß, Min-Chun Chen, Nils Wirges, Sinem Usluer, Rupert Oellinger, Svenja Lier, Michael Dudek, Tobias Madl, Martin Jastroch, Katja Steiger, Werner Schmitz, Henrik Einwächter, Roland M. Schmid
Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated
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Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors Cancer Res. (IF 12.5) Pub Date : 2024-07-11 Shiyun Xian, Xiaona Chen, Sihang Ren, Xiaolong Chen, Hangxiang Wang
Therapeutic strategies that induce inflammatory responses in immunologically “cold” tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the STING pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment
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Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression Cancer Res. (IF 12.5) Pub Date : 2024-07-11 Oihana Iriondo, Desirea Mecenas, Yilin Li, Christopher R. Chin, Amal Thomas, Aidan Moriarty, Rebecca Marker, Yiru Jess. Wang, Haley Hendrick, Yonatan Amzaleg, Veronica Ortiz, Matthew MacKay, Amber Dickerson, Grace Lee, Sevana Harotoonian, Bérénice A. Benayoun, Andrew Smith, Christopher E. Mason, Evanthia T. Roussos Torres, Remi Klotz, Min Yu
Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven
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An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression Cancer Res. (IF 12.5) Pub Date : 2024-07-11 Raunak Shrestha, Lisa N. Chesner, Meng Zhang, Stanley Zhou, Adam Foye, Arian Lundberg, Alana S. Weinstein, Martin Sjöström, Xiaolin Zhu, Thaidy Moreno-Rodriguez, Haolong Li, SU2C/PCF West Coast Prostate Cancer Dream Team, Joshi J. Alumkal, Rahul Aggarwal, Eric J. Small, Mathieu Lupien, David A. Quigley, Felix Y. Feng
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights
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CD47-SIRPα Blockade Sensitizes Head and Neck Squamous Cell Carcinoma to Cetuximab by Enhancing Macrophage Adhesion to Cancer Cells Cancer Res. (IF 12.5) Pub Date : 2024-07-03 Bolei Li, Yu Hao, Hongzhi He, Yu Fan, Biao Ren, Xian Peng, Xuedong Zhou, Lei Cheng
Developing effective treatments for patients with head and neck squamous cell carcinoma (HNSCC) is a significant challenge. Cetuximab, a first-line targeted therapy for HNSCC, exhibits limited efficacy. Here, we used pooled CRISPR screening to find targets that can synergize with cetuximab and identified CD47 as the leading candidate. Rather than inhibiting cancer cell proliferation, CD47 inhibition
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E-cadherin Induces Serine Synthesis to Support Progression and Metastasis of Breast Cancer Cancer Res. (IF 12.5) Pub Date : 2024-07-03 Geonhui Lee, Claudia Wong, Anna Cho, Junior J. West, Ashleigh J. Crawford, Gabriella C. Russo, Bishwa Ranjan Si, Jungwoo Kim, Lauren Hoffner, Cholsoon Jang, Moonjung Jung, Robert D. Leone, Konstantinos Konstantopoulos, Andrew J. Ewald, Denis Wirtz, Sangmoo Jeong
The loss of E-cadherin, an epithelial cell adhesion molecule, has been implicated in metastasis by mediating the epithelial-mesenchymal transition (EMT), which promotes invasion and migration of cancer cells. However, recent studies have demonstrated that E-cadherin supports the survival and proliferation of metastatic cancer cells. Here, we identified a metabolic role for E-cadherin in breast cancer
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Asparagine Dependency is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer Cancer Res. (IF 12.5) Pub Date : 2024-07-03 Young A. Yoo, Songhua Quan, William Yang, Qianyu Guo, Yara Rodríguez, Zachary R. Chalmers, Mary F. Dufficy, Barbara Lackie, Vinay Sagar, Kenji Unno, Mihai I. Truica, Navdeep S. Chandel, Sarki A. Abdulkadir
The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we showed here that TP53-altered prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS), the enzyme
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Integrative multi-omics analyses identify molecular subtypes of head and neck squamous cell carcinoma with distinct therapeutic vulnerabilities Cancer Res. (IF 12.5) Pub Date : 2024-07-03 Pengfei Diao, Yibin Dai, An Wang, Xiaoxuan Bu, Ziyu Wang, Jin Li, Yaping Wu, Hongbing Jiang, Yanling Wang, Jie Cheng
Substantial heterogeneity in molecular features, patient prognoses, and therapeutic responses in head and neck squamous cell carcinomas (HNSCC) highlights the urgent need to develop molecular classifications that reliably and accurately reflect tumor behavior and inform personalized therapy. Here, we leveraged the similarity network fusion bioinformatics approach to jointly analyze multi-omics datasets
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Adhesion GPCR ADGRE2 Maintains Proteostasis to Promote Progression in Acute Myeloid Leukemia Cancer Res. (IF 12.5) Pub Date : 2024-07-02 Deyu Huang, Zebin Yu, Huan Lu, Penglei Jiang, Xinyue Qian, Yingli Han, Pengxu Qian
Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein–coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic
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A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants Cancer Res. (IF 12.5) Pub Date : 2024-07-02 Yan Yang, Avvaru N. Suhasini, Zaoli Jiang, Nina Liu, Michael Rosconi, Bojie Zhang, Yinyin Li, Drew Dudgeon, Changhyun Seong, Steven Kim, Ashique Rafique, Tammy Huang, Sangram Bhosle, Pamela Krueger, Erica Ullman, William Olson, John C. Lin, Yang Shen, Christopher Daly
The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective
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The Warburg Effect Revisited through Blood and Electron Flow Cancer Res. (IF 12.5) Pub Date : 2024-07-02 Yahui Wang, Chi V. Dang
The Warburg effect describes the propensity of many cancers to consume glucose avidly and convert it to lactate in the presence of oxygen. The benefit of the Warburg effect on cancer cells remains enigmatic, particularly because extracellular disposal of incompletely oxidized lactate is wasteful. However, lactate is not discarded from the body, but rather recycled as pyruvate for metabolism through
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Clocking cancer immunotherapy responses Cancer Res. (IF 12.5) Pub Date : 2024-06-26 Catherine L. Wang, Xue Zhang, Chi Van. Dang
Two recent papers document that responses to immunotherapy are circadian and peak at the end of resting phase (evening) of mice with syngeneic and genetic models of cancers. The circadian effect is attributed to diurnal T cell trafficking through the endothelium on the one hand, and to the circadian expression of PD-L1 on myeloid suppressors on the other. Overall, it appears that tumor immunity as
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Proteomics Meets Dose-Response: A New Paradigm for Deciphering Drug Effects Cancer Res. (IF 12.5) Pub Date : 2024-06-26 Chenwei Wang, Bing Zhang
In a groundbreaking study, Eckert and colleagues introduce DecryptE, an innovative approach to dose-resolved proteomics that significantly advances our understanding of drug effects at the proteomic level. This method integrates cutting-edge sample preparation and mass spectrometry technologies, establishing a robust platform for high-throughput proteome analysis. DecryptE enables the quantification
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Multi-State Gene Cluster Switches Determine the Adaptive Mitochondrial And Metabolic Landscape of Breast Cancer Cancer Res. (IF 12.5) Pub Date : 2024-06-26 Michela Menegollo, Robert B. Bentham, Tiago Henriques, Seow Qi. Ng, Ziyu Ren, Clarinde Esculier, Sia Agarwal, Emily T.Y. Tong, Clement Lo, Sanjana Ilangovan, Zorka Szabadkai, Matteo Suman, Neill Patani, Avinash Ghanate, Kevin Bryson, Robert C. Stein, Mariia Yuneva, Gyorgy Szabadkai
Adaptive metabolic switches are proposed to underlie conversions between cellular states during normal development as well as in cancer evolution. Metabolic adaptations represent important therapeutic targets in tumors, highlighting the need to characterize the full spectrum, characteristics, and regulation of the metabolic switches. To investigate the hypothesis that metabolic switches associated
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Patterns of Aneuploidy and Signaling Consequences in Cancer Cancer Res. (IF 12.5) Pub Date : 2024-06-26 Nadja Zhakula-Kostadinova, Alison M. Taylor
Aneuploidy, or a change in the number of whole chromosomes or chromosome arms, is a near-universal feature of cancer. Chromosomes affected by aneuploidy are not random, with observed cancer-specific and tissue-specific patterns. Recent advances in genome engineering methods have allowed the creation of models with targeted aneuploidy events. These models can be used to uncover the downstream effects
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Targeting the TRIM14/USP14 Axis Enhances Immunotherapy Efficacy by Inducing Autophagic Degradation of PD-L1 Cancer Res. (IF 12.5) Pub Date : 2024-06-26 Di Liu, Mengqiu Li, Zhiyao Zhao, Liang Zhou, Feng Zhi, Zhiyong Guo, Jun Cui
Immunotherapy has greatly improved cancer treatment in recent years by harnessing the immune system to target cancer cells. The first immunotherapeutic agent approved by the US Food and Drug Administration (FDA) was interferon a (IFNa). Treatment with IFNa can lead to effective immune activation and attenuate tumor immune evasion, but persistent treatment has been shown to elicit immune suppressive
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Dotting out AML by targeting Fibrillarin Cancer Res. (IF 12.5) Pub Date : 2024-06-26 Hanzhi Luo, Michael G. Kharas
Dysregulated biomolecular condensates, formed through multivalent interactions among proteins and nucleic acids have been recently identified to drive tumorigenesis. In acute myeloid leukemia (AML), condensates driven by RNA-binding proteins (RBPs) alter transcriptional networks. Yang and colleagues performed a CRISPR screen and identified Fibrillarin (FBL) as a new driver in AML leukemogenesis. FBL
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Obesity Induces Temporally Regulated Alterations in the extracellular matrix that drive breast tumor invasion and metastasis Cancer Res. (IF 12.5) Pub Date : 2024-06-20 Sydney J. Conner, Hannah B. Borges, Justinne R. Guarin, Thomas J. Gerton, Anna Yui, Kenneth J. Salhany, Diamond N. Mensah, Grace A. Hamilton, Giang H. Le, Katherine C. Lew, Crystal Zhang, Madeleine J. Oudin
Obesity is associated with increased incidence and metastasis of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype. The extracellular matrix (ECM) is a major component of the tumor microenvironment that drives metastasis. To characterize the temporal effects of age and high-fat diet-driven weight gain on the ECM, we injected allograft tumor cells at 4-week intervals into mammary
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PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT Cancer Res. (IF 12.5) Pub Date : 2024-06-20 Wenchao Zhang, Wei Li, Chi Yin, Chengyao Feng, Binfeng Liu, Haodong Xu, Xin Jin, Chao Tu, Zhihong Li
Chemoresistance is one of the major causes of poor prognosis in osteosarcoma. Alternative therapeutic strategies for osteosarcoma are limited, indicating that increasing sensitivity to currently used chemotherapies could be an effective approach to improve patient outcomes. Using a kinome-wide CRISPR screen, we identified PRKDC as a critical determinant of doxorubicin (DOX) sensitivity in osteosarcoma
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RUVBL1/2 Blockade Targets YTHDF1 Activity to Suppress m6A-Dependent Oncogenic Translation and Colorectal Tumorigenesis Cancer Res. (IF 12.5) Pub Date : 2024-06-20 Danyu Chen, Fenfen Ji, Qiming Zhou, Henley Cheung, Yasi Pan, Harry Cheuk-Hay. Lau, Cong Liang, Zhenjie Yang, Pingmei Huang, Qinyao Wei, Alvin Ho-Kwan. Cheung, Wei Kang, Huarong Chen, Jun Yu, Chi Chun. Wong
The N6-methyladenosine (m6A) RNA binding protein YTHDF1 is frequently overexpressed in colorectal cancer (CRC) and drives chemotherapeutic resistance. To systematically identify druggable targets in CRC with high expression of YTHDF1, we employed a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets.RUVBL1/2 were overexpressed in primary CRC samples and represented independent
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Proteomic Profiling of Serum Extracellular Vesicles Identifies Diagnostic Signatures and Therapeutic Targets in Breast Cancer Cancer Res. (IF 12.5) Pub Date : 2024-06-20 Ganfei Xu, Rui Huang, Reziya Wumaier, Jiacheng Lyu, Minjing Huang, Yaya Zhang, Qingjian Chen, Wenting Liu, Mengyu Tao, Junjian Li, Zhonghua Tao, Bo Yu, Erxiang Xu, Lingfeng Wang, Guoying Yu, Olivier Gires, Lei Zhou, Wei Zhu, Chen Ding, Hongxia Wang
Analysis of extracellular vesicles (EVs) is a promising noninvasive liquid biopsy approach for breast cancer (BC) detection, prognosis, and therapeutic monitoring. A comprehensive understanding of the characteristics and proteomic composition of BC-specific EVs from human samples is required to realize the potential of this strategy. In this study, we applied a mass spectrometry-based, data-independent
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Human 3D ovarian cancer models reveal malignant cell intrinsic and extrinsic factors that influence CAR T cell activity Cancer Res. (IF 12.5) Pub Date : 2024-05-31 Joash D. Joy, Beatrice Malacrida, Florian Laforets, Panoraia Kotantaki, Eleni Maniati, Ranjit Manchanda, Alessandro Annibaldi, Sarah Hopkins, Ianire Garrobo-Calleja, Julien Gautrot, Frances R. Balkwill
In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment (TME). Here, we describe the modulation of CAR T cell activity by malignant cells and fibroblasts in human 3D in vitro cell models of increasing complexity
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VPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer Cancer Res. (IF 12.5) Pub Date : 2024-05-29 Tenzin Passang, Shuhua Wang, Hanwen Zhang, Fanyuan Zeng, Po-Chih Hsu, Wenxi Wang, Jian-Ming Li, Yuan Liu, Sruthi Ravindranathan, Gregory B. Lesinski, Edmund K. Waller
Pancreatic cancer (PDAC) harbors a complex tumor microenvironment (TME), and crosstalk between cells in the TME can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP
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Physical Activity Decreases Inflammation and Delays Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma Cancer Res. (IF 12.5) Pub Date : 2024-05-23 Valentina Pita-Grisanti, Ericka Vélez-Bonet, Kaylin Chasser, Zachary Hurst, Alexus Liette, Grace Vulic, Kelly Dubay, Ali Lahooti, Niharika Badi, Olivia Ueltschi, Kristyn Gumpper-Fedus, Hsiang-Yin Hsueh, Ila Lahooti, Myrriah Chavez-Tomar, Samantha Terhorst, Sue E. Knoblaugh, Lei Cao, Wei Huang, Christopher C. Coss, Thomas A. Mace, Fouad Choueiry, Alice Hinton, Stacey Culp, Jennifer M. Mitchell, Rosemarie
Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated
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Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance Cancer Res. (IF 12.5) Pub Date : 2024-05-22 Yi Sui, Teng Wang, Yanqing Mei, Ying Zhu, Wenyan Jiang, Jiayi Shen, Siyuan Yan, Wenjie Lu, Kewen Zhao, Jialin Mo, Chaochen Wang, Yujie Tang
Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted Smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional targeted therapies represent a promising direction for developing improved
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FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis Cancer Res. (IF 12.5) Pub Date : 2024-05-22 Dan Su, Ruobing Wang, Guangyu Chen, Chen Ding, Yueze Liu, JInxin Tao, Yuanyang Wang, Jiangdong Qiu, Wenhao Luo, Guihu Weng, Yang Gang, Taiping Zhang
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. Here, we identified FBXO32 as an oncogenic driver in PDAC.
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Large-scale alternative polyadenylation-wide association studies to identify putative cancer susceptibility genes Cancer Res. (IF 12.5) Pub Date : 2024-05-17 Xingyi Guo, Jie Ping, Yaohua Yang, Xinwan Su, Xiao-Ou Shu, Wanqing Wen, Zhishan Chen, Yunjing Zhang, Ran Tao, Guochong Jia, Jingni He, Qiuyin Cai, Qingrun Zhang, Graham G. Giles, Rachel Pearlman, Gad Rennert, Pavel Vodicka, Amanda Phipps, Stephen B. Gruber, Graham Casey, Ulrike Peters, Jirong Long, Weiqiang Lin, Wei Zheng
Alternative polyadenylation (APA) modulates mRNA processing in the 3’ untranslated regions (3’ UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. Herein, we conducted large alternative polyadenylation-wide association studies (APA-WAS) to investigate associations of APA levels with cancer risk. Genetic
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Allysine-Targeted Molecular MRI Enables Early Prediction of Chemotherapy Response in Pancreatic Cancer Cancer Res. (IF 12.5) Pub Date : 2024-05-17 Hua Ma, Shadi A. Esfahani, Shriya Krishna, Bahar Ataeinia, Iris Y. Zhou, Nicholas J. Rotile, Jonah Weigand-Whittier, Avery T. Boice, Andrew S. Liss, Kenneth K. Tanabe, Peter Caravan
Neoadjuvant therapy (NAT) is routinely used in pancreatic ductal adenocarcinoma (PDAC), but not all tumors respond to this treatment. Current clinical imaging techniques are not able to precisely evaluate and predict the response to neoadjuvant therapies over several weeks. A strong fibrotic reaction is a hallmark of a positive response, and during fibrogenesis allysine residues are formed on collagen
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Striking the Balance with a PD-L1×4–1BB Bispecific Antibody Cancer Res. (IF 12.5) Pub Date : 2024-05-15 JongHoon Ha, Adam J. Grippin, Betty Y.S. Kim, Wen Jiang
Antibody-based immune checkpoint blockade therapy has revolutionized the field of cancer immunotherapy, yet its efficacy remains limited in immunologically cold tumors. Combining checkpoint inhibitors with costimulatory agonists improves tumoricidal activity of T cells but also can lead to off-target hepatotoxicity. Although bispecific antibodies confer tumor selectivity to alleviate undesirable adverse
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Overcoming Nutrient Stress: Integrin αvβ3-Driven Metabolic Adaptation Supports Tumor Initiation Cancer Res. (IF 12.5) Pub Date : 2024-05-15 Elena Rainero
Nutrient stress accompanies several stages of tumor progression, including metastasis formation. Metabolic reprogramming is a hallmark of cancer, and it has been associated with stress tolerance and anchorage-independent cell survival. Adaptive responses are required to support cancer cell survival under these conditions. In this issue of Cancer Research, Nam and colleagues showed that the extracellular
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HiChIP-based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 that Confers Genetic Susceptibility to Gastroesophageal Cancer. Cancer Res. (IF 12.5) Pub Date : 2024-05-15 Ansley Gnanapragasam, Eftyhios Kirbizakis, Anna Li, Kyle H. White, Katelyn L. Mortenson, Juliana Cavalcante de Moura, Wajih Jawhar, Yifei Yan, Reilly Falter, Colleen Russett, Betty Giannias, Sophie Camilleri-Broët, Nicholas Bertos, Jonathan Cools-Lartigue, Livia Garzia, Veena Sangwan, Lorenzo E. Ferri, Xiaoyang Zhang, Swneke D. Bailey
Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNVs) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and the genes they modulate could help improve GEC prevention and treatment. Here, we used HiChIP against histone 3 lysine 27 acetylation
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The DRAP1/DR1 Repressor Complex Increases mTOR Activity to Promote Progression and Confer Everolimus Sensitivity in Triple-Negative Breast Cancer Cancer Res. (IF 12.5) Pub Date : 2024-05-15 Min-Ying Huang, Shu-Yuan Hu, Jia Dong, Ling Deng, Lisa Andriani, Xiao-Yan Ma, Yin-Ling Zhang, Fang-Lin Zhang, Zhi-Ming Shao, Da-Qiang Li
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Transcriptional dysregulation is a hallmark of cancer, and several transcriptional regulators have been demonstrated to contribute to cancer progression. Here, we identified upregulation of the transcriptional corepressor DRAP1 in TNBC, which was closely associated with poor recurrence-free survival in TNBC patients
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Estrogen induces LCAT to maintain cholesterol homeostasis and suppress hepatocellular carcinoma development Cancer Res. (IF 12.5) Pub Date : 2024-05-08 Wenzhi He, Min Wang, Xuechun Zhang, Yilan Wang, Dongli Zhao, Wenhua Li, Fang Lei, Min Peng, Zhonglin Zhang, Yufeng Yuan, Zan Huang
Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified LCAT as the most highly
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HDAC Inhibition Increases CXCL12 Secretion to Recruit Natural Killer Cells in Peripheral T Cell Lymphoma Cancer Res. (IF 12.5) Pub Date : 2024-05-08 Jiayan Zhu, Feng Wang, Lining Wang, Bo Dai, Guilin Xu, Luyao Zhao, Huimin Jiang, Wenhui Gao, Tingting Zhang, Chenxi Zhao, Yun-Xuan Li, Jiong Hu, Ke Li
Peripheral T cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Here, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3
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A Virus-Inspired Inhalable Liponanogel Induces Potent Antitumor Immunity and Regression in Metastatic Lung Tumors Cancer Res. (IF 12.5) Pub Date : 2024-05-08 Junyao Li, Lanqing Luo, Jia He, Jinchao Yu, Xinyan Li, Xueying Shen, Junxia Zhang, Sai Li, Jeffrey M. Karp, Rui Kuai
Pulmonary delivery of immunostimulatory agents such as poly(I:C) to activate double-stranded RNA sensors MDA5 and RIG-I within lung-resident antigen-presenting cells is a potential strategy to enhance antitumor immunity by promoting type I interferon secretion. However, following pulmonary delivery, poly(I:C) suffers from rapid degradation and poor endosomal escape, thus limiting its potency. Inspired
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The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression Cancer Res. (IF 12.5) Pub Date : 2024-05-08 Dandan Liu, Benliang Wei, Long Liang, Yue Sheng, Shengjie Sun, Xing Sun, Maohua Li, Haobo Li, Chaoying Yang, Yuanliang Peng, Yifang Xie, Chengcai Wen, Lu Chen, Xionghao Liu, Xiang Chen, Hong Liu, Jing Liu
Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Here, we found that the expression of retinoic acid receptor-related orphan receptor-α (RORA) is downregulated in melanoma patients and
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Single-cell analyses reveal the metabolic heterogeneity and plasticity of the tumor microenvironment during head and neck squamous cell carcinoma progression Cancer Res. (IF 12.5) Pub Date : 2024-05-08 Xiaoyan Meng, Yang Zheng, Lingfang Zhang, Peipei Liu, Zhonglong Liu, Yue He
Metabolic reprogramming is a hallmark of cancer. In addition to metabolic alterations in the tumor cells, multiple other metabolically active cell types in the tumor microenvironment (TME) contribute to the emergence of a tumor-specific metabolic milieu. Here, we defined the metabolic landscape of the TME during progression of head and neck squamous cell carcinoma (HNSCC) by performing single-cell
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Multiplexed Imaging Mass Cytometry Analysis Characterizes the Vascular Niche in Pancreatic Cancer Cancer Res. (IF 12.5) Pub Date : 2024-05-02 Jonathan Sussman, Nathalia Y. Kim, Samantha B. Kemp, Daniel Traum, Takeshi Katsuda, Benjamin M. Kahn, Jason Xu, Il-Kyu Kim, Cody Eskandarian, Devora Delman, Gregory L. Beatty, Klaus H. Kaestner, Amber L. Simpson, Ben Z. Stanger
Oncogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) is driven by complex interactions between the neoplastic component and the tumor microenvironment (TME), which includes immune, stromal, and parenchymal cells. In particular, most PDACs are characterized by a hypovascular and hypoxic environment that alters tumor cell behavior and limits the efficacy of chemotherapy and immunotherapy
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Hold the MYCrophone: MYC Invades Enhancers to Control Cancer Type Gene Programs Cancer Res. (IF 12.5) Pub Date : 2024-05-02 Kevin A. MacPherson-Hawthorne, Rosalie C. Sears
MYC is an oncogenic transcription factor that binds gene promoters to facilitate oncogenic gene expression. When overexpressed, as is the case in most human cancers, MYC also invades active enhancers—cis-regulatory elements that are critical for regulating gene expression. In previous studies, the regulatory significance of MYC enhancer invasion in cancer cells has been debated. In their study published
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Warburg Effect Reshapes Tumor Immunogenicity Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Jose A. Enríquez, María Mittelbrunn
Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift also modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported
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Exploring Novel Therapeutic Avenues for Chemotherapy Related Cognitive Impairment Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Jorg Dietrich, Michael W. Parsons, Emiliano Santarnecchi
Many cancer patients are at risk of developing cognitive symptoms that often become evident during or after cancer-directed therapy and may involve difficulties with attention, concentration, multitasking, executive function, and memory. Despite recent advances in identifying potential molecular and cellular mechanisms underlying cancer and chemotherapy-related cognitive impairment, there is generally
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IL1R2 blockade alleviates immunosuppression and potentiates anti-PD-1 efficacy in triple-negative breast cancer Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Jie Xia, Lixing Zhang, Xilei Peng, Juchuanli Tu, Siqin Li, Xueyan He, Fengkai Li, Jiankun Qiang, Haonan Dong, Qiaodan Deng, Cuicui Liu, Jiahui Xu, Rui Zhang, Quentin Liu, Guohong Hu, Chong Liu, Yi-Zhou Jiang, Zhi-Ming Shao, Ceshi Chen, Suling Liu
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Interleukin-1 receptor type 2 (IL1R2) promotes breast tumor-initiating cell (BTIC) self-renewal and tumor growth in TNBC, indicating that targeting it could improve patient treatment. Here, we observed that IL1R2 blockade strongly attenuated macrophage recruitment and the polarization of
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ACSM1 and ACSM3 regulate fatty acid metabolism to support prostate cancer growth and constrain ferroptosis Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Raj Kumar. Shrestha, Zeyad D. Nassar, Adrienne R. Hanson, Richard Iggo, Scott L. Townley, Jonas Dehairs, Chui Yan Mah, Madison Helm, Mohammadreza Alizadeh-Ghodsi, Marie Pickering, Bart Ghesquiere, Matthew J. Watt, Lake-Ee Quek, Andrew J. Hoy, Wayne D. Tilley, Johannes V. Swinnen, Lisa M. Butler, Luke A. Selth
Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate
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Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Sheng Yang, Dongsheng Zhang, Qingyang Sun, Hongxu Nie, Yue Zhang, Xiaowei Wang, Yuanjian Huang, Yueming Sun
Colorectal cancer (CRC) is one of the most common malignant tumors in humans, with liver metastasis being the primary cause of mortality. The epithelial-mesenchymal transition (EMT) process endows cancer cells with enhanced metastatic potential. To elucidate the cellular mechanisms driving EMT in CRC, we analyzed single-cell RNA-sequencing (scRNA-seq) data from 11 non-metastatic primary tumors (TnM)
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Comprehensive genetic profiling reveals frequent alterations of driver genes on the X chromosome in extranodal NK/T-cell lymphoma Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Yuta Ito, Amira Marouf, Yasunori Kogure, Junji Koya, Raphaël Liévin, Julie Bruneau, Mariko Tabata, Yuki Saito, Sumito Shingaki, Mitsuhiro Yuasa, Kentaro Yamaguchi, Koichi Murakami, Robert Weil, Manon Vavasseur, Guillaume P. Andrieu, Mehdi Latiri, Layla Veleanu, Michaël Dussiot, Isabelle André, Akshay Joshi, Chantal Lagresle-Peyrou, Aude Magerus, Sammara Chaubard, David Lavergne, Emmanuel Bachy, Erika
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. Here, we performed comprehensive genetic analysis of 177 ENKTCL cases to delineate the landscape of mutations, copy number alterations
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ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Ewa Sicinska, Vijaya Sudhakara Rao Kola, Joseph A. Kerfoot, Madeleine L. Taddei, Alyaa Al-Ibraheemi, Yi-Hsuan Hsieh, Alanna J. Church, Esther Landesman-Bollag, Yosef Landesman, Matthew L. Hemming
Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignancy driven by the ASPSCR1::TFE3 fusion. A better understanding of the mechanisms by which this oncogenic transcriptional regulator drives cancer growth is needed to help identify potential therapeutic targets. Here, we characterized the transcriptional and chromatin landscapes of ASPS tumors and preclinical models, identifying the essential
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Extracellular vesicles containing circMYBL1 induce CD44 in adenoid cystic carcinoma cells and pulmonary endothelial cells to promote lung metastasis Cancer Res. (IF 12.5) Pub Date : 2024-04-24 Min Fu, Qian Gao, Mian Xiao, Rui-Feng Li, Xin-Yi Sun, Sheng-Lin Li, Xin Peng, Xi-Yuan Ge
Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. Here, we identified a circRNA derived from MYBL1 pre-mRNA that accompanied overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased
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GPR1 and CMKLR1 control lipid metabolism to support development of clear cell renal cell carcinoma Cancer Res. (IF 12.5) Pub Date : 2024-04-19 Dazhi Wang, Iqbal Mahmud, Vijay S. Thakur, Sze Kiat Tan, Daniel G. Isom, David B. Lombard, Mark L. Gonzalgo, Oleksandr N. Kryvenko, Philip L. Lorenzi, Vanina T. Tcheuyap, James Brugarolas, Scott M. Welford
Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1
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CD58 alterations govern antitumor immune responses by inducing PD-L1 and IDO in diffuse large B-cell lymphoma Cancer Res. (IF 12.5) Pub Date : 2024-04-18 Xiyue Xu, Yidan Zhang, Yaxiao Lu, Xiaoyan Zhang, Cuicui Zhao, Jiesong Wang, Qingpei Guan, Yingfang Feng, Meng Gao, Jingwei Yu, Zheng Song, Xia Liu, Zahra Golchehre, Lanfang Li, Weicheng Ren, Qiang Pan-Hammarström, Huilai Zhang, Xianhuo Wang
Recurrent abnormalities in immune surveillance-related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and natural killer (NK) cells and is recurrently mutated and deleted in DLBCL, suggesting it may play a role in regulating antitumor immunity. Herein, we comprehensively analyzed
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CRISPR-Cas9 screening identifies KRAS-induced COX-2 as a driver of immunotherapy resistance in lung cancer Cancer Res. (IF 12.5) Pub Date : 2024-04-18 Jesse Boumelha, Andrea de Castro, Nourdine Bah, Hongui Cha, Sophie de Carné Trécesson, Sareena Rana, Mona Tomaschko, Panayiotis Anastasiou, Edurne Mugarza, Christopher Moore, Robert Goldstone, Philip East, Kevin Litchfield, Se-Hoon Lee, Miriam Molina-Arcas, Julian Downward
Oncogenic KRAS impairs anti-tumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of how oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms
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CD106 in tumor-specific exhausted CD8+ T cells mediates immunosuppression by inhibiting TCR signaling Cancer Res. (IF 12.5) Pub Date : 2024-04-18 Yuto Naoi, Takao Morinaga, Joji Nagasaki, Ryo Ariyasu, Youki Ueda, Kazuo Yamashita, Wenhao Zhou, Shusuke Kawashima, Katsushige Kawase, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yu Kawahara, Yasuhiro Nakamura, Yukiko Kiniwa, Osamu Yamasaki, Satoshi Fukushima, Masahito Kawazu, Yutaka Suzuki, Hiroyoshi Nishikawa, Toyoyuki Hanazawa, Mizuo Ando, Takashi Inozume, Yosuke
T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106
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PARP-ish: Gaps in Molecular Understanding and Clinical Trials Targeting PARP Exacerbate Racial Disparities in Prostate Cancer Cancer Res. (IF 12.5) Pub Date : 2024-04-18 Moriah Cunningham, Matthew J. Schiewer
PARP is a nuclear enzyme with a major function in the DNA damage response. PARP inhibitors (PARPi) have been developed for treating tumors harboring homologous recombination repair (HRR) defects that lead to a dependency on PARP. There are currently three PARPi approved for use in advanced prostate cancer (PCa), and several others are in clinical trials for this disease. Recent clinical trial results
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Deuterium metabolic imaging differentiates glioblastoma metabolic subtypes and detects early response to chemoradiotherapy Cancer Res. (IF 12.5) Pub Date : 2024-04-18 Jacob Chen Ming Low, Jianbo Cao, Friederike Hesse, Alan J. Wright, Anastasia Tsyben, Islam Alshamleh, Richard Mair, Kevin M. Brindle
Metabolic subtypes of glioblastoma have different prognoses and responses to treatment. Deuterium metabolic imaging with 2H-labeled substrates is a potential approach to stratify patients into metabolic subtypes for targeted treatment. Here, we used 2H magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) measurements of [6,6’-2H2]glucose metabolism to identify metabolic subtypes and