Cancer Cell

Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF Publication date: Available online 8 April 2019 Source: Cancer Cell Author(s): María Teresa Blasco, Carolina Navas, Guillermo Martín-Serrano, Osvaldo Graña-Castro, Carmen G. Lechuga, Laura Martín-Díaz, Magdolna Djurec, Jing Li, Lucia Morales-Cacho, Laura Esteban-Burgos, Javier Perales-Patón, Emilie Bousquet-Mur, Eva Castellano, Harrys K.C. Jacob, Lavinia Cabras, Monica Musteanu, Matthias Drosten, Sagrario Ortega, Francisca Mulero, Bruno Sainz Summary Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients. Graphical Abstract

Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties Publication date: Available online 4 April 2019 Source: Cancer Cell Author(s): Xiangqian Kong, Jie Chen, Wenbing Xie, Stephen M. Brown, Yi Cai, Kaichun Wu, Daiming Fan, Yongzhan Nie, Srinivasan Yegnasubramanian, Rochelle L. Tiedemann, Yong Tao, Ray-Whay Chiu Yen, Michael J. Topper, Cynthia A. Zahnow, Hariharan Easwaran, Scott B. Rothbart, Limin Xia, Stephen B. Baylin Summary UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents. Graphical Abstract

Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets Publication date: Available online 28 March 2019 Source: Cancer Cell Author(s): Luca Cassetta, Stamatina Fragkogianni, Andrew H. Sims, Agnieszka Swierczak, Lesley M. Forrester, Hui Zhang, Daniel Y.H. Soong, Tiziana Cotechini, Pavana Anur, Elaine Y. Lin, Antonella Fidanza, Martha Lopez-Yrigoyen, Michael R. Millar, Alexandra Urman, Zhichao Ai, Paul T. Spellman, E. Shelley Hwang, J. Michael Dixon, Lisa Wiechmann, Lisa M. Coussens Summary The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes. Graphical Abstract

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis Publication date: Available online 28 March 2019 Source: Cancer Cell Author(s): Michael A. Augello, Deli Liu, Lesa D. Deonarine, Brian D. Robinson, Dennis Huang, Suzan Stelloo, Mirjam Blattner, Ashley S. Doane, Elissa W.P. Wong, Yu Chen, Mark A. Rubin, Himisha Beltran, Olivier Elemento, Andries M. Bergman, Wilbert Zwart, Andrea Sboner, Noah Dephoure, Christopher E. Barbieri Summary Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Notably, this cistrome shift was associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways unique to this tumor subclass. Collectively, these data credential CHD1 as a tumor suppressor in the prostate that constrains AR binding/function to limit tumor progression. Graphical Abstract

Intraclonal Plasticity in Mammary Tumors Revealed through Large-Scale Single-Cell Resolution 3D Imaging Publication date: Available online 28 March 2019 Source: Cancer Cell Author(s): Anne C. Rios, Bianca D. Capaldo, François Vaillant, Bhupinder Pal, Ravian van Ineveld, Caleb A. Dawson, Yunshun Chen, Emma Nolan, Nai Yang Fu, 3DTCLSM Group, Felicity C. Jackling, Sapna Devi, David Clouston, Lachlan Whitehead, Gordon K. Smyth, Scott N. Mueller, Geoffrey J. Lindeman, Jane E. Visvader Summary Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Expression profiling of clones arising in Pten/Trp53-deficient tumors identified distinct molecular signatures. Strikingly, most clones harbored cells that had undergone an epithelial-to-mesenchymal transition, indicating widespread, inherent plasticity. Hence, an integrative pipeline that combines lineage tracing, 3D imaging, and clonal RNA sequencing technologies offers a comprehensive path for studying mechanisms underlying heterogeneity in whole tumors. Graphical Abstract

KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer Publication date: Available online 21 March 2019 Source: Cancer Cell Author(s): Wenting Liao, Michael J. Overman, Adam T. Boutin, Xiaoying Shang, Di Zhao, Prasenjit Dey, Jiexi Li, Guocan Wang, Zhengdao Lan, Jun Li, Ming Tang, Shan Jiang, Xingdi Ma, Peiwen Chen, Riham Katkhuda, Krittiya Korphaisarn, Deepavali Chakravarti, Andrew Chang, Denise J. Spring, Qing Chang Summary The biological functions and mechanisms of oncogenic KRASG12D (KRAS∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS∗ represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS∗-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS∗-IRF2-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC. Graphical Abstract

Evolutionary Trajectories of IDHWT Glioblastomas Reveal a Common Path of Early Tumorigenesis Instigated Years ahead of Initial Diagnosis Publication date: Available online 21 March 2019 Source: Cancer Cell Author(s): Verena Körber, Jing Yang, Pankaj Barah, Yonghe Wu, Damian Stichel, Zuguang Gu, Michael Nai Chung Fletcher, David Jones, Bettina Hentschel, Katrin Lamszus, Jörg Christian Tonn, Gabriele Schackert, Michael Sabel, Jörg Felsberg, Angela Zacher, Kerstin Kaulich, Daniel Hübschmann, Christel Herold-Mende, Andreas von Deimling, Michael Weller Summary We studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response for isocitrate dehydrogenase (IDH)-wild-type glioblastoma, a rapidly regrowing tumor. We inferred the evolutionary trajectories of matched pairs of primary and relapsed tumors based on deep whole-genome-sequencing data. This analysis suggests both a distant origin of de novo glioblastoma, up to 7 years before diagnosis, and a common path of early tumorigenesis, with one or more of chromosome 7 gain, 9p loss, or 10 loss, at tumor initiation. TERT promoter mutations often occurred later as a prerequisite for rapid growth. In contrast to this common early path, relapsed tumors acquired no stereotypical pattern of mutations and typically regrew from oligoclonal origins, suggesting sparse selective pressure by therapeutic measures. Graphical Abstract

ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer Publication date: 18 March 2019 Source: Cancer Cell, Volume 35, Issue 3 Author(s): Laura Cato, Jonas de Tribolet-Hardy, Irene Lee, Jaice T. Rottenberg, Ilsa Coleman, Diana Melchers, René Houtman, Tengfei Xiao, Wei Li, Takuma Uo, Shihua Sun, Nane C. Kuznik, Bettina Göppert, Fatma Ozgun, Martin E. van Royen, Adriaan B. Houtsmuller, Raga Vadhi, Prakash K. Rao, Lewyn Li, Steven P. Balk Summary Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Expression of the ARv7-repressed targets and ARv7 protein expression are negatively correlated and predicts for outcome in PCa patients. Our results provide insights into the role of ARv7 in CRPC and define a set of potential biomarkers for tumors dependent on ARv7. Graphical Abstract

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer Publication date: 18 March 2019 Source: Cancer Cell, Volume 35, Issue 3 Author(s): Miguel Reina-Campos, Juan F. Linares, Angeles Duran, Thekla Cordes, Antoine L'Hermitte, Mehmet G. Badur, Munveer S. Bhangoo, Phataraporn K. Thorson, Alicia Richards, Tarmo Rooslid, Dolores C. Garcia-Olmo, Syongh Y. Nam-Cha, Antonio S. Salinas-Sanchez, Ken Eng, Himisha Beltran, David A. Scott, Christian M. Metallo, Jorge Moscat, Maria T. Diaz-Meco Summary Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa. Graphical Abstract

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia Publication date: 18 March 2019 Source: Cancer Cell, Volume 35, Issue 3 Author(s): Eric Wang, Sydney X. Lu, Alessandro Pastore, Xufeng Chen, Jochen Imig, Stanley Chun-Wei Lee, Kathryn Hockemeyer, Yohana E. Ghebrechristos, Akihide Yoshimi, Daichi Inoue, Michelle Ki, Hana Cho, Lillian Bitner, Andreas Kloetgen, Kuan-Ting Lin, Taisuke Uehara, Takashi Owa, Raoul Tibes, Adrian R. Krainer, Omar Abdel-Wahab Summary RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations. Graphical Abstract