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Cancer Cell

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https://www.readbyqxmd.com/read/28162975/comprehensive-molecular-characterization-of-pheochromocytoma-and-paraganglioma
#1
Lauren Fishbein, Ignaty Leshchiner, Vonn Walter, Ludmila Danilova, A Gordon Robertson, Amy R Johnson, Tara M Lichtenberg, Bradley A Murray, Hans K Ghayee, Tobias Else, Shiyun Ling, Stuart R Jefferys, Aguirre A de Cubas, Brandon Wenz, Esther Korpershoek, Antonio L Amelio, Liza Makowski, W Kimryn Rathmell, Anne-Paule Gimenez-Roqueplo, Thomas J Giordano, Sylvia L Asa, Arthur S Tischler, Karel Pacak, Katherine L Nathanson, Matthew D Wilkerson
We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1...
February 2, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28089890/single-chromosome-gains-commonly-function-as-tumor-suppressors
#2
Jason M Sheltzer, Julie H Ko, John M Replogle, Nicole C Habibe Burgos, Erica S Chung, Colleen M Meehl, Nicole M Sayles, Verena Passerini, Zuzana Storchova, Angelika Amon
Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness...
December 29, 2016: Cancer Cell
https://www.readbyqxmd.com/read/28196596/chemosensitive-relapse-in-small-cell-lung-cancer-proceeds-through-an-ezh2-slfn11-axis
#3
Eric E Gardner, Benjamin H Lok, Valentina E Schneeberger, Patrice Desmeules, Linde A Miles, Paige K Arnold, Andy Ni, Inna Khodos, Elisa de Stanchina, Thuyen Nguyen, Julien Sage, John E Campbell, Scott Ribich, Natasha Rekhtman, Afshin Dowlati, Pierre P Massion, Charles M Rudin, John T Poirier
Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196595/characterization-of-human-cancer-cell-lines-by-reverse-phase-protein-arrays
#4
Jun Li, Wei Zhao, Rehan Akbani, Wenbin Liu, Zhenlin Ju, Shiyun Ling, Christopher P Vellano, Paul Roebuck, Qinghua Yu, A Karina Eterovic, Lauren A Byers, Michael A Davies, Wanleng Deng, Y N Vashisht Gopal, Guo Chen, Erika M von Euw, Dennis Slamon, Dylan Conklin, John V Heymach, Adi F Gazdar, John D Minna, Jeffrey N Myers, Yiling Lu, Gordon B Mills, Han Liang
Cancer cell lines are major model systems for mechanistic investigation and drug development. However, protein expression data linked to high-quality DNA, RNA, and drug-screening data have not been available across a large number of cancer cell lines. Using reverse-phase protein arrays, we measured expression levels of ∼230 key cancer-related proteins in >650 independent cell lines, many of which have publically available genomic, transcriptomic, and drug-screening data. Our dataset recapitulates the effects of mutated pathways on protein expression observed in patient samples, and demonstrates that proteins and particularly phosphoproteins provide information for predicting drug sensitivity that is not available from the corresponding mRNAs...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196594/inactivation-of-interferon-receptor-promotes-the-establishment-of-immune-privileged-tumor-microenvironment
#5
Kanstantsin V Katlinski, Jun Gui, Yuliya V Katlinskaya, Angelíca Ortiz, Riddhita Chakraborty, Sabyasachi Bhattacharya, Christopher J Carbone, Daniel P Beiting, Melanie A Girondo, Amy R Peck, Ellen Puré, Priya Chatterji, Anil K Rustgi, J Alan Diehl, Constantinos Koumenis, Hallgeir Rui, Serge Y Fuchs
Refractoriness of solid tumors, including colorectal cancers (CRCs), to immunotherapies is attributed to the immunosuppressive tumor microenvironment that protects malignant cells from cytotoxic T lymphocytes (CTLs). We found that downregulation of the type I interferon receptor chain IFNAR1 occurs in human CRC and mouse models of CRC. Downregulation of IFNAR1 in tumor stroma stimulated CRC development and growth, played a key role in formation of the immune-privileged niche, and predicted poor prognosis in human CRC patients...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196593/liquid-biopsies-what-we-do-not-know-yet
#6
REVIEW
Alberto Bardelli, Klaus Pantel
The inherent molecular heterogeneity of metastatic tumors and the ability of cancer genomes to dynamically evolve are not properly captured by tissue specimens. Analysis of cell-free DNA and circulating tumor cells has the potential to change clinical practice by exploiting blood rather than tissue as a source of information. Liquid biopsies are already used to monitor disease response and track the emergence of drug resistance. The suitability of blood-based molecular profiles for early detection and monitoring minimal residual disease is being evaluated...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196592/awakening-of-schlafen11-to-tackle-chemotherapy-resistance-in-sclc
#7
Katrien Berns, Anton Berns
Chemotherapy resistance arises invariably in small cell lung cancer (SCLC). In this issue of Cancer Cell, Gardner et al. find that in some SCLC, EZH2 mediates resistance via downregulation of Schlafen11 (SLFN11). Combining EZH2 inhibition with chemotherapy effectively overcomes drug resistance of xenografted SCLC, holding promise for new treatment paradigms.
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196591/nuclear-pkc%C3%AE-ect2-rac1-and-ribosome-biogenesis-a-novel-axis-in-lung-tumorigenesis
#8
Martin J Baker, Mariana Cooke, Marcelo G Kazanietz
The RhoGEF Ect2 controls cell division and exerts oncogenic functions in multiple cancers. In this issue of Cancer Cell, Justilien et al. report that Ect2 is required for lung tumorigenesis and identified a role for this GEF in ribosomal RNA (rRNA) synthesis that is mediated by Rac1 and PKCι-dependent phosphorylation.
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196590/singling-out-chromosome-gains-in-tumor-evolution
#9
Ryan M Naylor, Jan M van Deursen
In this issue of Cancer Cell, Sheltzer et al. shed new light on Theodor Boveri's century-old hypothesis by demonstrating that aneuploidy characterized by single-chromosome gains acts to suppress tumorigenesis and that aneuploidy itself is a nidus for genomic instability.
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196589/an-oncogenic-role-for-the-ubiquitin-ligase-ube2o-by-targeting-ampk-%C3%AE-2-for-degradation
#10
D Grahame Hardie
There has been controversy regarding the role of AMPK in cancer, some of which may be due to functional differences between isoforms. In this issue of Cancer Cell, Vila et al. report that UBE2O, a ubiquitin ligase overexpressed in some human cancers, specifically triggers the ubiquitination and degradation of AMPK-α2.
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196588/ifnar1-degradation-a-new-mechanism-for-tumor-immune-evasion
#11
Romina E Araya, Romina S Goldszmid
Type I interferons have been shown to play a major role in anti-cancer immunity. In this issue of Cancer Cell, Katlinski et al. describe tumor-induced degradation of type I interferon receptor IFNAR1 chain as a new immune-evasion mechanism in colorectal cancers. Stabilizing IFNAR1 inhibits tumor growth and improves immunotherapy efficacy.
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196587/pheochromocytomas-and-paragangliomas-genetically-diverse-and-minimalist-all-at-once
#12
Patricia L M Dahia
Pheochromocytomas and paragangliomas are infrequent, genetically heterogeneous neuroendocrine tumors. In this issue of Cancer Cell, Fishbein et al. report novel driver genes, pathogenic mechanisms, and markers of malignancy. Notably, the new findings support the long-held view that these tumors distinctively arise from a single driver event, either inherited or acquired.
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28162974/a-ube2o-ampk%C3%AE-2-axis-that-promotes-tumor-initiation-and-progression-offers-opportunities-for-therapy
#13
Isabelle K Vila, Yixin Yao, Goeun Kim, Weiya Xia, Hyejin Kim, Sun-Joong Kim, Mi-Kyung Park, James P Hwang, Enrique González-Billalabeitia, Mien-Chie Hung, Su Jung Song, Min Sup Song
UBE2O is localized in the 17q25 locus, which is known to be amplified in human cancers, but its role in tumorigenesis remains undefined. Here we show that Ube2o deletion in MMTV-PyVT or TRAMP mice profoundly impairs tumor initiation, growth, and metastasis, while switching off the metabolic reprogramming of tumor cells. Mechanistically, UBE2O specifically targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Notably, inactivation of AMPKα2, but not AMPKα1, abrogates the tumor attenuation caused by UBE2O loss, while treatment with rapamycin or inhibition of HIF1α ablates UBE2O-dependent tumor biology...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28110998/ect2-dependent-rrna-synthesis-is-required-for-kras-trp53-driven-lung-adenocarcinoma
#14
Verline Justilien, Syed A Ali, Lee Jamieson, Ning Yin, Adrienne D Cox, Channing J Der, Nicole R Murray, Alan P Fields
The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28089889/myc-drives-progression-of-small-cell-lung-cancer-to-a-variant-neuroendocrine-subtype-with-vulnerability-to-aurora-kinase-inhibition
#15
Gurkan Mollaoglu, Matthew R Guthrie, Stefanie Böhm, Johannes Brägelmann, Ismail Can, Paul M Ballieu, Annika Marx, Julie George, Christine Heinen, Milind D Chalishazar, Haixia Cheng, Abbie S Ireland, Kendall E Denning, Anandaroop Mukhopadhyay, Jeffery M Vahrenkamp, Kristofer C Berrett, Timothy L Mosbruger, Jun Wang, Jessica L Kohan, Mohamed E Salama, Benjamin L Witt, Martin Peifer, Roman K Thomas, Jason Gertz, Jane E Johnson, Adi F Gazdar, Robert J Wechsler-Reya, Martin L Sos, Trudy G Oliver
Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low "variant" subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28073006/bcl9l-dysfunction-impairs-caspase-2-expression-permitting-aneuploidy-tolerance-in-colorectal-cancer
#16
Carlos López-García, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28073005/simultaneous-inhibition-of-pi3k%C3%AE-and-pi3k%C3%AE-induces-abc-dlbcl-regression-by-blocking-bcr-dependent-and-independent-activation-of-nf-%C3%AE%C2%BAb-and-akt
#17
Juliane Paul, Maurice Soujon, Antje M Wengner, Sabine Zitzmann-Kolbe, Andrea Sturz, Katja Haike, Koh Hui Keng Magdalene, Sze Huey Tan, Martin Lange, Soo Yong Tan, Dominik Mumberg, Soon Thye Lim, Karl Ziegelbauer, Ningshu Liu
Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79(mut), CARD11(mut), TNFAIP3(mut), or MYD88(mut)...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28073004/epigenetic-sirna-and-chemical-screens-identify-setd8-inhibition-as-a-therapeutic-strategy-for-p53-activation-in-high-risk-neuroblastoma
#18
Veronica Veschi, Zhihui Liu, Ty C Voss, Laurent Ozbun, Berkley Gryder, Chunhua Yan, Ying Hu, Anqi Ma, Jian Jin, Sharlyn J Mazur, Norris Lam, Barbara K Souza, Giuseppe Giannini, Gordon L Hager, Cheryl H Arrowsmith, Javed Khan, Ettore Appella, Carol J Thiele
Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4(K20me1) methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53(K382me1), leading to activation of the p53 canonical pathway...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28073003/employing-metabolism-to-improve-the-diagnosis-and-treatment-of-pancreatic-cancer
#19
REVIEW
Christopher J Halbrook, Costas A Lyssiotis
Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28073002/cancer-and-apoptosis-who-is-built-to-last
#20
Douglas R Green
Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state.
January 9, 2017: Cancer Cell
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