CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity
CTL–associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and ...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Andreas Herrmann, Christoph Lahtz, Toshikage Nagao, Joo Y. Song, Wing C. Chan, Heehyoung Lee, Chanyu Yue, Thomas Look, Ronȷa Mulfarth, Wenzhao Li, Kurt Jenkins, John Williams, Lihua E. Budde, Stephen Forman, Larry Kwak, Thomas Blankenstein, Hua Yu Tags: Microenvironment and Immunology Source Type: research
Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors
Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GIST. Most GISTs eventually acquire imatinib resistance due to secondary mutations in the KIT kinase domain, but it is unclear whether these genomic resistance mechanisms require other cellular adaptations to create a clinically meaningful imatinib-resistant state. Using phospho-RTK and immunoblot assays, we demonstrate activation of KIT and insulin receptor (IR) in imatinib-res...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Weicai Chen, Ye Kuang, Hai-Bo Qiu, Zhifa Cao, Yuqing Tu, Qing Sheng, Grant Eilers, Quan He, Hai-Long Li, Meijun Zhu, Yuexiang Wang, Rongqing Zhang, Yeqing Wu, Fanguo Meng, Jonathan A. Fletcher, Wen-Bin Ou Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome
High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory ...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Peng Li, Evan Wuthrick, Jeff A. Rappaport, Crystal Kraft, Jieru E. Lin, Glen Marszalowicz, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Scott A. Waldman Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer
Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-dri...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Jonathan M. Cooper, Yi-Hung Ou, Elizabeth A. McMillan, Rachel M. Vaden, Aubhishek Zaman, Brian O. Bodemann, Gurbani Makkar, Bruce A. Posner, Michael A. White Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma
Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1–induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to r...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Yan Liu, Yuyang Li, Xiaoen Wang, Feiyang Liu, Peng Gao, Max M. Quinn, Fei Li, Ashley A. Merlino, Cyril Benes, Qingsong Liu, Nathanael S. Gray, Kwok-Kin Wong Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy
Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%–80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%–20% killing) and adult fibroblasts (20 years old; ∼10%–30% killing). Old fibroblasts also displayed significantly increased (2–4-fold) stea...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Kranti A. Mapuskar, Kyle H. Flippo, Joshua D. Schoenfeld, Dennis P. Riley, Stefan Strack, Taher Abu Hejleh, Muhammad Furqan, Varun Monga, Frederick E. Domann, John M. Buatti, Prabhat C. Goswami, Douglas R. Spitz, Bryan G. Allen Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells
Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells b...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Kwon-Ho Song, Chel Hun Choi, Hyo-Jung Lee, Se Jin Oh, Seon Rang Woo, Soon-Oh Hong, Kyung Hee Noh, Hanbyoul Cho, Eun Joo Chung, Jae-Hoon Kim, Joon-Yong Chung, Stephen M. Hewitt, Seungki Baek, Kyung-Mi Lee, Cassian Yee, Minjoo Son, Chih-Ping Mao, T.C. Wu, T Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis
We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of mal...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Dina S. Stepanova, Galina Semenova, Yin-Ming Kuo, Andrew J. Andrews, Sylwia Ammoun, C. Oliver Hanemann, Jonathan Chernoff Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Posttranscriptional Regulation of PARG mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors
The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair vi...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Saswati N. Chand, Mahsa Zarei, Matthew J. Schiewer, Akshay R. Kamath, Carmella Romeo, Shruti Lal, Joseph A. Cozzitorto, Avinoam Nevler, Laura Scolaro, Eric Londin, Wei Jiang, Nicole Meisner-Kober, Michael J. Pishvaian, Karen E. Knudsen, Charles J. Yeo, Jo Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression
In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared with normal brain tissue and that this event tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the t...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Xueran Chen, Huihui Ma, Zhen Wang, Shangrong Zhang, Haoran Yang, Zhiyou Fang Tags: Tumor and Stem Cell Biology Source Type: research
SOX5/6/21 Prevent Oncogene-Driven Transformation of Brain Stem Cells
Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Idha Kurtsdotter, Daniȷal Topcic, Alexandra Karlen, Bhumica Singla, Daniel W. Hagey, Maria Bergsland, Peter Siesȷo, Monica Nister, Joseph W. Carlson, Veronique Lefebvre, Oscar Persson, Johan Holmberg, Jonas Muhr Tags: Tumor and Stem Cell Biology Source Type: research
Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBP{beta} Signaling
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Jinlong Yin, Young Taek Oh, Jeong-Yub Kim, Sung Soo Kim, Eunji Choi, Tae Hoon Kim, Jun Hee Hong, Nakho Chang, Hee Jin Cho, Jason K. Sa, Jeong Cheol Kim, Hyung Joon Kwon, Saewhan Park, Weiwei Lin, Ichiro Nakano, Ho-Shin Gwak, Heon Yoo, Seung-Hoon Lee, Jeon Tags: Tumor and Stem Cell Biology Source Type: research
Survival of Head and Neck Cancer Cells Relies upon LZK Kinase-Mediated Stabilization of Mutant p53
Head and neck squamous cell carcinoma (HNSCC) includes epithelial cancers of the oral and nasal cavity, larynx, and pharynx and accounts for ∼350,000 deaths per year worldwide. Smoking-related HNSCC is associated with few targetable mutations but is defined by frequent copy-number alteration, the most common of which is gain at 3q. Critical 3q target genes have not been conclusively determined for HNSCC. Here, we present data indicating that MAP3K13 (encoding LZK) is an amplified driver gene in HNSCC. Copy-number gain at 3q resulted in increased MAP3K13 mRNA in HNSCC tumor samples and cell lines. Silencing LZK reduced ce...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Zoe C. Edwards, Eleanor W. Trotter, Pedro Torres-Ayuso, Phil Chapman, Henry M. Wood, Katherine Nyswaner, John Brognard Tags: Tumor and Stem Cell Biology Source Type: research
MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells
Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor–initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding si...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Xiuxing Wang, Zhi Huang, Qiulian Wu, Briana C. Prager, Stephen C. Mack, Kailin Yang, Leo J.Y. Kim, Ryan C. Gimple, Yu Shi, Sisi Lai, Qi Xie, Tyler E. Miller, Christopher G. Hubert, Anne Song, Zhen Dong, Wenchao Zhou, Xiaoguang Fang, Zhe Zhu, Vaidehi Mahad Tags: Tumor and Stem Cell Biology Source Type: research
Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III
Greater than 50% of estrogen receptor (ER)–positive breast cancers coexpress the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive patient-derived xenograft models of breast cancer, where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated ...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Jessica Finlay-Schultz, Austin E. Gillen, Heather M. Brechbuhl, Joshua J. Ivie, Shawna B. Matthews, Britta M. Jacobsen, David L. Bentley, Peter Kabos, Carol A. Sartorius Tags: Tumor and Stem Cell Biology Source Type: research
