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Cancer Cell

Francesca Menghi, Floris P Barthel, Vinod Yadav, Ming Tang, Bo Ji, Zhonghui Tang, Gregory W Carter, Yijun Ruan, Ralph Scully, Roel G W Verhaak, Jos Jonkers, Edison T Liu
The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. TDPs with ∼11 kb TDs feature loss of TP53 and BRCA1. TDPs with ∼231 kb and ∼1.7 Mb TDs associate with CCNE1 pathway activation and CDK12 disruptions, respectively. We demonstrate that p53 and BRCA1 conjoint abrogation drives TDP induction by generating short-span TDP mammary tumors in genetically modified mice lacking them...
June 29, 2018: Cancer Cell
Marat S Pavlyukov, Hai Yu, Soniya Bastola, Mutsuko Minata, Victoria O Shender, Yeri Lee, Suojun Zhang, Jia Wang, Svetlana Komarova, Jun Wang, Shinobu Yamaguchi, Heba Allah Alsheikh, Junfeng Shi, Dongquan Chen, Ahmed Mohyeldin, Sung-Hak Kim, Yong Jae Shin, Ksenia Anufrieva, Evgeniy G Evtushenko, Nadezhda V Antipova, Georgij P Arapidi, Vadim Govorun, Nikolay B Pestov, Mikhail I Shakhparonov, L James Lee, Do-Hyun Nam, Ichiro Nakano
Aggressive cancers such as glioblastoma (GBM) contain intermingled apoptotic cells adjacent to proliferating tumor cells. Nonetheless, intercellular signaling between apoptotic and surviving cancer cells remain elusive. In this study, we demonstrate that apoptotic GBM cells paradoxically promote proliferation and therapy resistance of surviving tumor cells by secreting apoptotic extracellular vesicles (apoEVs) enriched with various components of spliceosomes. apoEVs alter RNA splicing in recipient cells, thereby promoting their therapy resistance and aggressive migratory phenotype...
June 8, 2018: Cancer Cell
Matthew S Waitkus, Bill H Diplas, Hai Yan
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development...
May 14, 2018: Cancer Cell
Daniel Zingg, Julien Debbache, Rodrigo Peña-Hernández, Ana T Antunes, Simon M Schaefer, Phil F Cheng, Dario Zimmerli, Jessica Haeusel, Raquel R Calçada, Eylul Tuncer, Yudong Zhang, Raphaël Bossart, Kwok-Kin Wong, Konrad Basler, Reinhard Dummer, Raffaella Santoro, Mitchell P Levesque, Lukas Sommer
Human melanomas frequently harbor amplifications of EZH2. However, the contribution of EZH2 to melanoma formation has remained elusive. Taking advantage of murine melanoma models, we show that EZH2 drives tumorigenesis from benign BrafV600E - or NrasQ61K -expressing melanocytes by silencing of genes relevant for the integrity of the primary cilium, a signaling organelle projecting from the surface of vertebrate cells. Consequently, gain of EZH2 promotes loss of primary cilia in benign melanocytic lesions. In contrast, blockade of EZH2 activity evokes ciliogenesis and cilia-dependent growth inhibition in malignant melanoma...
July 9, 2018: Cancer Cell
Lan Fang, Hongqi Teng, Yilin Wang, Guanghong Liao, Linjun Weng, Yaxu Li, Xinbo Wang, Jiali Jin, Chenchen Jiao, Lei Chen, Xiaoping Peng, Jiayu Chen, Yongzhi Yang, Houqin Fang, Dongyan Han, Cheng Li, Xueling Jin, Shihao Zhang, Zhongchen Liu, Min Liu, Qing Wei, Lujian Liao, Xin Ge, Bin Zhao, Dawang Zhou, Huan-Long Qin, Jun Zhou, Ping Wang
YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis...
July 9, 2018: Cancer Cell
Athena Georgilis, Sabrina Klotz, Christopher J Hanley, Nicolas Herranz, Benedikt Weirich, Beatriz Morancho, Ana Carolina Leote, Luana D'Artista, Suchira Gallage, Marco Seehawer, Thomas Carroll, Gopuraja Dharmalingam, Keng Boon Wee, Marco Mellone, Joaquim Pombo, Danijela Heide, Ernesto Guccione, Joaquín Arribas, Nuno L Barbosa-Morais, Mathias Heikenwalder, Gareth J Thomas, Lars Zender, Jesús Gil
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1...
July 9, 2018: Cancer Cell
Clemens A Schmitt
Cellular senescence serves as a barrier to tumor development and a principle effector of anti-cancer therapy, but the largely pro-inflammatory senescence-associated secretory phenotype (SASP) may drive tumor promotion and contribute to age-related pathologies. In this issue of Cancer Cell, Georgilis et al. present SASP-deprived senescence as a potential therapeutic perspective.
July 9, 2018: Cancer Cell
Hanlin Zeng, Aparna Jorapur, A Hunter Shain, Ursula E Lang, Rodrigo Torres, Yuntian Zhang, Andrew S McNeal, Thomas Botton, Jue Lin, Matthew Donne, Ingmar N Bastian, Richard Yu, Jeffrey P North, Laura Pincus, Beth S Ruben, Nancy M Joseph, Iwei Yeh, Boris C Bastian, Robert L Judson
Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression...
July 9, 2018: Cancer Cell
A Hunter Shain, Nancy M Joseph, Richard Yu, Jamal Benhamida, Shanshan Liu, Tarl Prow, Beth Ruben, Jeffrey North, Laura Pincus, Iwei Yeh, Robert Judson, Boris C Bastian
We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas...
July 9, 2018: Cancer Cell
Peter K Jackson
EZH2 is frequently amplified in human melanomas. In this issue of Cancer Cell, Zingg et al. find that EZH2 overexpression silences genes for the primary cilium, causing deciliation, Wnt pathway activation, and progression of BrafV600E - or NrasQ61N -driven melanomas, thus defining a tumor-suppressor role for cilia in cancer.
July 9, 2018: Cancer Cell
Zev A Binder, Amy Haseley Thorne, Spyridon Bakas, E Paul Wileyto, Michel Bilello, Hamed Akbari, Saima Rathore, Sung Min Ha, Logan Zhang, Cole J Ferguson, Sonika Dahiya, Wenya Linda Bi, David A Reardon, Ahmed Idbaih, Joerg Felsberg, Bettina Hentschel, Michael Weller, Stephen J Bagley, Jennifer J D Morrissette, MacLean P Nasrallah, Jianhui Ma, Ciro Zanca, Andrew M Scott, Laura Orellana, Christos Davatzikos, Frank B Furnari, Donald M O'Rourke
We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFRA289D/T/V ). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFRA289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFRA289V and dependent on ERK-mediated expression of matrix metalloproteinase-1...
July 9, 2018: Cancer Cell
Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Andrea Sartore-Bianchi, Benedetta Mussolin, Andrea Cassingena, Cosimo Martino, Richard B Lanman, Rebecca J Nagy, Stephen Fairclough, Giuseppe Rospo, Giorgio Corti, Alice Bartolini, Pamela Arcella, Monica Montone, Francesca Lodi, Annalisa Lorenzato, Alice Vanzati, Emanuele Valtorta, Giovanni Cappello, Andrea Bertotti, Sara Lonardi, Vittorina Zagonel, Francesco Leone, Mariangela Russo, Antonella Balsamo, Mauro Truini, Federica Di Nicolantonio, Alessio Amatu, Erica Bonazzina, Silvia Ghezzi, Daniele Regge, Angelo Vanzulli, Livio Trusolino, Salvatore Siena, Silvia Marsoni, Alberto Bardelli
Targeting HER2 is effective in 24% of ERBB2 amplified metastatic colorectal cancer; however, secondary resistance occurs in most of the cases. We studied the evolution of individual metastases during treatment to discover spatially resolved determinants of resistance. Circulating tumor DNA (ctDNA) analysis identified alterations associated with resistance in the majority of refractory patients. ctDNA profiles and lesion-specific radiographic reports revealed organ- or metastasis-private evolutionary patterns...
July 9, 2018: Cancer Cell
Chelsea L Dieck, Gannie Tzoneva, Farhad Forouhar, Zachary Carpenter, Alberto Ambesi-Impiombato, Marta Sánchez-Martín, Renate Kirschner-Schwabe, Scott Lew, Jayaraman Seetharaman, Liang Tong, Adolfo A Ferrando
Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2...
July 9, 2018: Cancer Cell
Gaurav Pathria, Ze'ev A Ronai
One of the remaining challenges in treating melanoma is its strong propensity to metastasize. Thus, there is considerable interest in understanding the alterations that drive progression of the disease. In this issue of Cancer Cell, Shain et al. and Zheng et al. provide insights implicating p16INK4A in melanoma invasiveness.
July 9, 2018: Cancer Cell
Montserrat Rojo de la Vega, Eli Chapman, Donna D Zhang
The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor...
July 9, 2018: Cancer Cell
Marc A Morgan, Ali Shilatifard
In this issue of Cancer Cell, McBride and colleagues report that the synovial sarcoma SS18-SSX fusion drives BAF complex recruitment to bivalent domains repressed by PRC2 complex to orchestrate aberrant transcriptional activation. Redistribution of BAF localization is a major driver of synovial sarcoma proliferation and presents a promising therapeutic target.
June 11, 2018: Cancer Cell
Colleen R Reczek, Navdeep S Chandel
To avoid reactive oxygen species (ROS)-induced cell death, cancer cells increase their antioxidant defense system. In this issue of Cancer Cell, Takahashi et al. identify a novel, non-canonical oxidative stress defense mechanism involving TRPA1, a redox-sensitive Ca2+ channel, and the upregulation of anti-apoptotic pathways to promote cancer cell survival.
June 11, 2018: Cancer Cell
Sarah M Greenblatt, Na Man, Pierre-Jacques Hamard, Takashi Asai, Daniel Karl, Concepcion Martinez, Daniel Bilbao, Vasileios Stathais, Anna McGrew-Jermacowicz, Stephanie Duffort, Madhavi Tadi, Ezra Blumenthal, Samantha Newman, Ly Vu, Ye Xu, Fan Liu, Stephan C Schurer, Michael T McCabe, Ryan G Kruger, Mingjiang Xu, Feng-Chun Yang, Daniel Tenen, Justin Watts, Francisco Vega, Stephen D Nimer
Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis...
June 11, 2018: Cancer Cell
Ewa Gogola, Alexandra A Duarte, Julian R de Ruiter, Wouter W Wiegant, Jonas A Schmid, Roebi de Bruijn, Dominic I James, Sergi Guerrero Llobet, Daniel J Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J Ogilvie, Marcel van Vugt, Lodewyk F A Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism...
June 11, 2018: Cancer Cell
Debanjan Dhar, Laura Antonucci, Hayato Nakagawa, Ju Youn Kim, Elisabeth Glitzner, Stefano Caruso, Shabnam Shalapour, Ling Yang, Mark A Valasek, Sooyeon Lee, Kerstin Minnich, Ekihiro Seki, Jan Tuckermann, Maria Sibilia, Jessica Zucman-Rossi, Michael Karin
How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response...
June 11, 2018: Cancer Cell
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