ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures
Publication date: Available online 17 October 2019Source: Cancer CellAuthor(s): Zulekha A. Qadeer, David Valle-Garcia, Dan Hasson, Zhen Sun, April Cook, Christie Nguyen, Aroa Soriano, Anqi Ma, Lyra M. Griffiths, Maged Zeineldin, Dan Filipescu, Luz Jubierre, Asif Chowdhury, Orla Deevy, Xiang Chen, David B. Finkelstein, Armita Bahrami, Elizabeth Stewart, Sara Federico, Soledad GallegoSummaryATRX alterations occur at high frequency in neuroblastoma of adolescents and young adults. Particularly intriguing are the large N-terminal deletions of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) that generate in-frame fusion (...
Source: Cancer Cell - October 18, 2019 Category: Cancer & Oncology Source Type: research

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG
Publication date: Available online 17 October 2019Source: Cancer CellAuthor(s): Jamie N. Anastas, Barry M. Zee, Jay H. Kalin, Mirhee Kim, Robyn Guo, Sanda Alexandrescu, Mario Andres Blanco, Stefanie Giera, Shawn M. Gillespie, Jayanta Das, Muzhou Wu, Sarah Nocco, Dennis M. Bonal, Quang-De Nguyen, Mario L. Suva, Bradley E. Bernstein, Rhoda Alani, Todd R. Golub, Philip A. Cole, Mariella G. FilbinSummaryH3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysin...
Source: Cancer Cell - October 18, 2019 Category: Cancer & Oncology Source Type: research

Venetoclax in Lymphoid Malignancies: New Insights, More to Learn
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Rachel Thijssen, Andrew W. RobertsIn this issue of Cancer Cell, Guièza et al. describe that overexpression of the pro-survival protein MCL1 and cellular energy metabolic reprogramming can contribute to resistance to the BCL2 inhibitor venetoclax in patients with chronic lymphocytic leukemia. This adds a new dimension to understanding of secondary clinical resistance to venetoclax. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

PRC2 Plays Red Light, Green Light with MHC-I and CD8+ T Cells
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Johnathan R. WhetstineIn this issue of Cancer Cell, Burr et al. report that PRC2 plays a conserved role in silencing antigen presentation and processing genes and, in turn, CD8+ T cell activation. Furthermore, PRC2-targeted therapeutics overcome gene silencing and promote tumor clearance by cytotoxic T cells. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Thrown for a Loop: Awakening BORIS to Evade ALK Inhibition Therapy
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Esther R. Berko, Yael P. MosséMechanisms of acquired resistance to ALK inhibition therapy in neuroblastoma have not yet been elucidated. In a recent issue of Nature, Debruyne et al. demonstrate that resistant MYCN-amplified ALK-mutated neuroblastoma cells overexpress BORIS, resulting in wide-ranging changes in chromatin interaction and transcriptional reprogramming. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Acquired Resistance Is Oncogene and Drug Agnostic
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Robert C. DoebeleRecent approvals of TRK inhibitors have demonstrated the success of a tumor agnostic approach to oncogene-targeted therapy across cancers. Collective data from acquired resistance studies suggest that resistance mechanisms, which include both kinase domain mutations and bypass signaling via RTK-RAS-RAF-MAPK pathways, frequently recur regardless of tumor type, oncogene, and drug. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Toward the Early Detection of Cancer by Decoding the Epigenetic and Environmental Fingerprints of Cell-Free DNA
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Ymke van der Pol, Florent MouliereWidespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. Circulating tumor DNA is commonly detected though the presence of genetic alterations, but only a minor fraction of tumor-derived cell-free DNA (cfDNA) fragments exhibit mutations. The cellular processes occurring in cancer development mark the chromatin. These epigenetic marks are reflected by modifications in the cfDNA methylation, fragment size, and structure. In this review, we describe how going b...
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
Publication date: Available online 3 October 2019Source: Cancer CellAuthor(s): Jacqulyne P. Robichaux, Yasir Y. Elamin, R.S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark RoutbortSummaryWe characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to elev...
Source: Cancer Cell - October 5, 2019 Category: Cancer & Oncology Source Type: research

Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer
Publication date: Available online 3 October 2019Source: Cancer CellAuthor(s): Lichun Ma, Maria O. Hernandez, Yongmei Zhao, Monika Mehta, Bao Tran, Michael Kelly, Zachary Rae, Jonathan M. Hernandez, Jeremy L. Davis, Sean P. Martin, David E. Kleiner, Stephen M. Hewitt, Kris Ylaya, Bradford J. Wood, Tim F. Greten, Xin Wei WangSummaryCellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and betw...
Source: Cancer Cell - October 5, 2019 Category: Cancer & Oncology Source Type: research

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer
Publication date: Available online 26 September 2019Source: Cancer CellAuthor(s): Marian L. Burr, Christina E. Sparbier, Kah Lok Chan, Yih-Chih Chan, Ariena Kersbergen, Enid Y.N. Lam, Elizabeth Azidis-Yates, Dane Vassiliadis, Charles C. Bell, Omer Gilan, Susan Jackson, Lavinia Tan, Stephen Q. Wong, Sebastian Hollizeck, Ewa M. Michalak, Hannah V. Siddle, Michael T. McCabe, Rab K. Prinjha, Glen R. Guerra, Benjamin J. SolomonSummaryLoss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb re...
Source: Cancer Cell - September 28, 2019 Category: Cancer & Oncology Source Type: research

Dynamic Incorporation of Histone H3 Variants into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization
Publication date: Available online 26 September 2019Source: Cancer CellAuthor(s): Ana P. Gomes, Didem Ilter, Vivien Low, Adam Rosenzweig, Zih-Jie Shen, Tanya Schild, Martin A. Rivas, Ekrem E. Er, Dylan R. McNally, Anders P. Mutvei, Julie Han, Yi-Hung Ou, Paola Cavaliere, Edouard Mullarky, Michal Nagiec, Sejeong Shin, Sang-Oh Yoon, Noah Dephoure, Joan Massagué, Ari M. MelnickSummaryMetastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation...
Source: Cancer Cell - September 28, 2019 Category: Cancer & Oncology Source Type: research

Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants
Publication date: Available online 19 September 2019Source: Cancer CellAuthor(s): Christopher A. Eide, Matthew S. Zabriskie, Samantha L. Savage Stevens, Orlando Antelope, Nadeem A. Vellore, Hein Than, Anna Reister Schultz, Phillip Clair, Amber D. Bowler, Anthony D. Pomicter, Dongqing Yan, Anna V. Senina, Wang Qiang, Todd W. Kelley, Philippe Szankasi, Michael C. Heinrich, Jeffrey W. Tyner, Delphine Rea, Jean-Michel Cayuela, Dong-Wook KimSummaryBCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved ...
Source: Cancer Cell - September 20, 2019 Category: Cancer & Oncology Source Type: research

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies
Publication date: Available online 19 September 2019Source: Cancer CellAuthor(s): Romain Guièze, Vivian M. Liu, Daniel Rosebrock, Alexis A. Jourdain, María Hernández-Sánchez, Aina Martinez Zurita, Jing Sun, Elisa Ten Hacken, Kaitlyn Baranowski, Philip A. Thompson, Jin-Mi Heo, Zachary Cartun, Ozan Aygün, J. Bryan Iorgulescu, Wandi Zhang, Giulia Notarangelo, Dimitri Livitz, Shuqiang Li, Matthew S. Davids, Anat BiranSummaryMitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to thi...
Source: Cancer Cell - September 20, 2019 Category: Cancer & Oncology Source Type: research

LMO2 as a Biomarker for Hypersensitivity to Genotoxic Therapy
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Claudio Scuoppo, Shan ZhaIn this issue of Cancer Cell, Parvin and colleagues identify the expression of LMO2 as a biomarker for DNA repair defects in lymphomas. Using isogenic cell lines and xenografts, the authors show that expression of LMO2 predicts sensitivity to PARP inhibition, especially in combination with genotoxic therapy. (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Colon Cancer: Epithelial Notch Signaling Recruits Neutrophils to Drive Metastasis
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Jürgen RulandIn this issue of Cancer Cell, Jackstadt et al. report that pathological Notch signaling in colorectal cancer (CRC) cells can initiate a neutrophil-dependent, TGF-β-mediated cascade that leads to metastatic disease. Inhibition of this pathway with clinically relevant compounds blocks metastatic spread in a developed murine model of CRC. (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Recruit or Reboot? How Does Anti-PD-1 Therapy Change Tumor-Infiltrating Lymphocytes?
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Margaret K. Callahan, Jedd D. WolchokIt has been widely assumed that PD-1 blockade works by reinvigorating (“rebooting”) pre-existing exhausted tumor-infiltrating ilymphocytes (TILs). A recent study challenges this paradigm, demonstrating that the majority of tumor-specific TILs after anti-PD-1 treatment have TCRs not identified in the tumor pre-therapy, suggesting they are newly recruited post-therapy. (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Tracy O'Connor, Xiaolan Zhou, Jan Kosla, Arlind Adili, Maria Garcia Beccaria, Elena Kotsiliti, Dominik Pfister, Anna-Lena Johlke, Ankit Sinha, Roman Sankowski, Markus Schick, Richard Lewis, Nikolaos Dokalis, Bastian Seubert, Bastian Höchst, Donato Inverso, Danijela Heide, Wenlong Zhang, Petra Weihrich, Katrin ManskeSummaryHow lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated...
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Passenger Hotspot Mutations in Cancer
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Julian M. Hess, Andre Bernards, Jaegil Kim, Mendy Miller, Amaro Taylor-Weiner, Nicholas J. Haradhvala, Michael S. Lawrence, Gad GetzSummaryCurrent statistical models for assessing hotspot significance do not properly account for variation in site-specific mutability, thereby yielding many false-positives. We thus (i) detail a Log-normal-Poisson (LNP) background model that accounts for this variability in a manner consistent with models of mutagenesis; (ii) use it to show that passenger hotspots arise from all common mutational processes; a...
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Rene Jackstadt, Sander R. van Hooff, Joshua D. Leach, Xabier Cortes-Lavaud, Jeroen O. Lohuis, Rachel A. Ridgway, Valérie M. Wouters, Jatin Roper, Timothy J. Kendall, Campbell S. Roxburgh, Paul G. Horgan, Colin Nixon, Craig Nourse, Matthias Gunzer, William Clark, Ann Hedley, Omer H. Yilmaz, Mamunur Rashid, Peter Bailey, Andrew V. BiankinSummaryThe metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium le...
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

UNR/CSDE1 Drives a Post-transcriptional Program to Promote Melanoma Invasion and Metastasis
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Laurence Wurth, Panagiotis Papasaikas, David Olmeda, Nadine Bley, Guadalupe T. Calvo, Santiago Guerrero, Daniela Cerezo-Wallis, Javier Martinez-Useros, María García-Fernández, Stefan Hüttelmaier, Maria S. Soengas, Fátima Gebauer (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Brian Krug, Nicolas De Jay, Ashot S. Harutyunyan, Shriya Deshmukh, Dylan M. Marchione, Paul Guilhamon, Kelsey C. Bertrand, Leonie G. Mikael, Melissa K. McConechy, Carol C.L. Chen, Sima Khazaei, Robert F. Koncar, Sameer Agnihotri, Damien Faury, Benjamin Ellezam, Alexander G. Weil, Josie Ursini-Siegel, Daniel D. De Carvalho, Peter B. Dirks, Peter W. Lewis (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey W. Taub (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse
Publication date: Available online 29 August 2019Source: Cancer CellAuthor(s): Liguo Zhang, Xuelian He, Xuezhao Liu, Feng Zhang, L. Frank Huang, Andrew S. Potter, Lingli Xu, Wenhao Zhou, Tao Zheng, Zaili Luo, Kalen P. Berry, Allison Pribnow, Stephanie M. Smith, Christine Fuller, Blaise V. Jones, Maryam Fouladi, Rachid Drissi, Zeng-Jie Yang, W. Clay Gustafson, Marc RemkeSummaryProgenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) me...
Source: Cancer Cell - August 30, 2019 Category: Cancer & Oncology Source Type: research

The Dual Roles of the Atypical Protein Kinase Cs in Cancer
Publication date: Available online 29 August 2019Source: Cancer CellAuthor(s): Miguel Reina-Campos, Maria T. Diaz-Meco, Jorge MoscatAtypical protein kinase C (aPKC) isozymes, PKCλ/ι and PKCζ, are now considered fundamental regulators of tumorigenesis. However, the specific separation of functions that determine their different roles in cancer is still being unraveled. Both aPKCs have pleiotropic context-dependent functions that can translate into tumor-promoter or -suppressive functions. Here, we review early and more recent literature to discuss how the different tumor types, and their microenvironments, ...
Source: Cancer Cell - August 30, 2019 Category: Cancer & Oncology Source Type: research

GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism
Publication date: Available online 22 August 2019Source: Cancer CellAuthor(s): Laura Mondragón, Rana Mhaidly, Gian Marco De Donatis, Marie Tosolini, Pascal Dao, Anthony R. Martin, Caroline Pons, Johanna Chiche, Marie Jacquin, Véronique Imbert, Emma Proïcs, Laurent Boyer, Anne Doye, Frédéric Luciano, Jaap G. Neels, Frédéric Coutant, Nicole Fabien, Laura Sormani, Camila Rubio-Patiño, Jozef P. BossowskiSummaryGAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model ove...
Source: Cancer Cell - August 23, 2019 Category: Cancer & Oncology Source Type: research

LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL
Publication date: Available online 22 August 2019Source: Cancer CellAuthor(s): Salma Parvin, Ariel Ramirez-Labrada, Shlomzion Aumann, XiaoQing Lu, Natalia Weich, Gabriel Santiago, Elena M. Cortizas, Eden Sharabi, Yu Zhang, Isidro Sanchez-Garcia, Andrew J. Gentles, Evan Roberts, Daniel Bilbao-Cortes, Francisco Vega, Jennifer R. Chapman, Ramiro E. Verdun, Izidore S. LossosSummaryDeficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B...
Source: Cancer Cell - August 23, 2019 Category: Cancer & Oncology Source Type: research

Mechanisms of Leukemia Evolution: Lessons from a Congenital Syndrome
Publication date: 12 August 2019Source: Cancer Cell, Volume 36, Issue 2Author(s): Yehudit Birger, Ruth Shiloh, Shai IzraeliStudies of the mechanisms of acute leukemia transformation from a preleukemic state in humans are hampered by the absence of clinical preleukemia syndromes. In this issue of Cancer Cell, Labuhn et al. provide a functional genomics view on the leukemic evolution from congenital preleukemia in children with Down syndrome. (Source: Cancer Cell)
Source: Cancer Cell - August 13, 2019 Category: Cancer & Oncology Source Type: research

A Positive Step toward Understanding Double-Negative Metastatic Prostate Cancer
Publication date: 12 August 2019Source: Cancer Cell, Volume 36, Issue 2Author(s): Michael M. ShenIn this issue of Cancer Cell, Su et al. demonstrate that epigenetic reprogramming by Polycomb Repressive Complex 1 (PRC1) promotes an inflammatory tumor microenvironment in a subtype of metastatic prostate cancer, and show that a PRC1 inhibitor can synergize with immune checkpoint inhibitors to suppress metastasis in mouse models. (Source: Cancer Cell)
Source: Cancer Cell - August 13, 2019 Category: Cancer & Oncology Source Type: research

The Sly Oncogene: FOXA1 Mutations in Prostate Cancer
Publication date: 12 August 2019Source: Cancer Cell, Volume 36, Issue 2Author(s): Neel Shah, Myles BrownFOXA1 mutations occur frequently in prostate cancer and are associated with a worse clinical outcome. However, the mechanism by which these mutations act was until now largely unknown. Two recent publications clearly demonstrate that FOXA1 acts as an oncogene in prostate cancer and delineate the phenotypic effects of distinct classes of FOXA1 alterations. (Source: Cancer Cell)
Source: Cancer Cell - August 13, 2019 Category: Cancer & Oncology Source Type: research

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation
Publication date: 12 August 2019Source: Cancer Cell, Volume 36, Issue 2Author(s): Jia Yi Fong, Luca Pignata, Pierre-Alexis Goy, Kimihito Cojin Kawabata, Stanley Chun-Wei Lee, Cheryl M. Koh, Daniele Musiani, Enrico Massignani, Andriana G. Kotini, Alex Penson, Cheng Mun Wun, Yudao Shen, Megan Schwarz, Diana HP. Low, Alexander Rialdi, Michelle Ki, Heike Wollmann, Slim Mzoughi, Florence Gay, Christine ThompsonSummaryCancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have le...
Source: Cancer Cell - August 13, 2019 Category: Cancer & Oncology Source Type: research

Protein Kinase Cι and Wnt/β-Catenin Signaling: Alternative Pathways to Kras/Trp53-Driven Lung Adenocarcinoma
We report that mouse LSL-KrasG12D;Trp53fl/fl (KP)-mediated lung adenocarcinoma (LADC) tumorigenesis can proceed through both PKCι-dependent and PKCι-independent pathways. The predominant pathway involves PKCι-dependent transformation of bronchoalveolar stem cells (BASCs). However, KP mice harboring conditional knock out Prkci alleles (KPI mice) develop LADC tumors through PKCι-independent transformation of Axin2+ alveolar type 2 (AT2) stem cells. Transformed growth of KPI, but not KP, tumors is blocked by Wnt pathway inhibition in vitro and in vivo. Furthermore, a KPI-derived genomic signature...
Source: Cancer Cell - August 2, 2019 Category: Cancer & Oncology Source Type: research

A Pharmacogenomic Landscape in Human Liver Cancers
Publication date: Available online 1 August 2019Source: Cancer CellAuthor(s): Zhixin Qiu, Hong Li, Zhengtao Zhang, Zhenfeng Zhu, Sheng He, Xujun Wang, Pengcheng Wang, Jianjie Qin, Liping Zhuang, Wei Wang, Fubo Xie, Ying Gu, Keke Zou, Chao Li, Chun Li, Chenhua Wang, Jin Cen, Xiaotao Chen, Yajing Shu, Zhao ZhangSummaryLiver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to e...
Source: Cancer Cell - August 2, 2019 Category: Cancer & Oncology Source Type: research

Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy
Publication date: Available online 18 July 2019Source: Cancer CellAuthor(s): Heng-Huan Lee, Ying-Nai Wang, Weiya Xia, Chia-Hung Chen, Kun-Ming Rau, Leiguang Ye, Yongkun Wei, Chao-Kai Chou, Shao-Chun Wang, Meisi Yan, Chih-Yen Tu, Te-Chun Hsia, Shu-Fen Chiang, K.S. Clifford Chao, Ignacio I. Wistuba, Jennifer L. Hsu, Gabriel N. Hortobagyi, Mien-Chie HungSummaryReactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with patient response, which presents a clinical challenge to stratify ...
Source: Cancer Cell - July 20, 2019 Category: Cancer & Oncology Source Type: research

The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression
Publication date: Available online 18 July 2019Source: Cancer CellAuthor(s): Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I. Scher, Ouathek Ouerfelli, Filippo G. GiancottiSummaryThe mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL2 as the top prometast...
Source: Cancer Cell - July 20, 2019 Category: Cancer & Oncology Source Type: research

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome
Publication date: Available online 11 July 2019Source: Cancer CellAuthor(s): Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey TaubSummaryMyeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combin...
Source: Cancer Cell - July 13, 2019 Category: Cancer & Oncology Source Type: research

The Stromal and Immune Landscape of Colorectal Cancer Progression during Anti-EGFR Therapy
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Irene Catalano, Livio TrusolinoIn this issue of Cancer Cell, Woolston et al. show that colorectal cancers that become refractory to initially effective anti-EGFR therapy contain an abundance of stromal and immune cells, irrespective of the contextual presence of resistance-conferring mutations. This reconfiguration puts forward therapeutic opportunities for patients who relapse on EGFR-targeting treatment. (Source: Cancer Cell)
Source: Cancer Cell - July 10, 2019 Category: Cancer & Oncology Source Type: research

M-TAP Dance: Targeting PRMT1 and PRMT5 Family Members to Push Cancer Cells Over the Edge
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Nivine Srour, Sofiane Y. Mersaoui, Stéphane RichardIn this issue of Cancer Cell, Fedoriw and colleagues characterize a potent reversible inhibitor of type I PRMTs, GSK3368715, with anti-proliferative effects on numerous cancer types. Using a combination of GSK3368715 with PRMT5 inhibitors, the authors show that a threshold of overall arginine methylation reduction needs to be achieved for synergistic anti-tumor activity. (Source: Cancer Cell)
Source: Cancer Cell - July 10, 2019 Category: Cancer & Oncology Source Type: research

Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading?
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Stefan Mereiter, Meritxell Balmaña, Diana Campos, Joana Gomes, Celso A. ReisThis review provides insights on the impact of glycosylation in cancer biology and its influence in the current approaches of targeted cancer therapies in the clinical setting. The roles of glycosylation in cancer signaling, tumor progression, and metastasis are reviewed as well as glycans and glycan-binding proteins in tumor immunomodulation. Moreover, the latest reports on glycans influencing targeted therapeutic approaches in cancer are summarized. Finally, we ...
Source: Cancer Cell - July 10, 2019 Category: Cancer & Oncology Source Type: research

Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Nikolas G. Balanis, Katherine M. Sheu, Favour N. Esedebe, Saahil J. Patel, Bryan A. Smith, Jung Wook Park, Salwan Alhani, Brigitte N. Gomperts, Jiaoti Huang, Owen N. Witte, Thomas G. GraeberSummarySmall-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN me...
Source: Cancer Cell - July 10, 2019 Category: Cancer & Oncology Source Type: research

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Andrew Woolston, Khurum Khan, Georgia Spain, Louise J. Barber, Beatrice Griffiths, Reyes Gonzalez-Exposito, Lisa Hornsteiner, Marco Punta, Yatish Patil, Alice Newey, Sonia Mansukhani, Matthew N. Davies, Andrew Furness, Francesco Sclafani, Clare Peckitt, Mirta Jiménez, Kyriakos Kouvelakis, Romana Ranftl, Ruwaida Begum, Isma RanaSummaryDespite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance lands...
Source: Cancer Cell - July 10, 2019 Category: Cancer & Oncology Source Type: research

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Patrick Sin-Chan, Iqra Mumal, Tannu Suwal, Ben Ho, Xiaolian Fan, Irtisha Singh, Yuchen Du, Mei Lu, Neilket Patel, Jonathon Torchia, Dean Popovski, Maryam Fouladi, Paul Guilhamon, Jordan R. Hansford, Sarah Leary, Lindsey M. Hoffman, Jean M. Mulcahy Levy, Alvaro Lassaletta, Palma Solano-Paez, Eloy RivasSummaryEmbryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogen...
Source: Cancer Cell - July 10, 2019 Category: Cancer & Oncology Source Type: research

Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia
Publication date: 8 July 2019Source: Cancer Cell, Volume 36, Issue 1Author(s): Irène Baccelli, Yves Gareau, Bernhard Lehnertz, Stéphane Gingras, Jean-François Spinella, Sophie Corneau, Nadine Mayotte, Simon Girard, Mélanie Frechette, Valérie Blouin-Chagnon, Koryne Leveillé, Isabel Boivin, Tara MacRae, Jana Krosl, Clarisse Thiollier, Vincent-Philippe Lavallée, Evgeny Kanshin, Thierry Bertomeu, Jasmin Coulombe-Huntington, Corinne St-DenisSummaryTo identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritini...
Source: Cancer Cell - July 10, 2019 Category: Cancer & Oncology Source Type: research

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss
Publication date: Available online 27 June 2019Source: Cancer CellAuthor(s): Andrew Fedoriw, Satyajit R. Rajapurkar, Shane O'Brien, Sarah V. Gerhart, Lorna H. Mitchell, Nicholas D. Adams, Nathalie Rioux, Trupti Lingaraj, Scott A. Ribich, Melissa B. Pappalardi, Niyant Shah, Jenny Laraio, Yan Liu, Michael Butticello, Chris L. Carpenter, Caretha Creasy, Susan Korenchuk, Michael T. McCabe, Charles F. McHugh, Raman NagarajanSummaryType I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhib...
Source: Cancer Cell - June 29, 2019 Category: Cancer & Oncology Source Type: research

RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance
Publication date: Available online 27 June 2019Source: Cancer CellAuthor(s): Daniël A. Lionarons, David C. Hancock, Sareena Rana, Philip East, Christopher Moore, Miguel M. Murillo, Joana Carvalho, Bradley Spencer-Dene, Eleanor Herbert, Gordon Stamp, Djamil Damry, Dinis P. Calado, Ian Rosewell, Ralph Fritsch, Richard R. Neubig, Miriam Molina-Arcas, Julian DownwardSummaryRAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated...
Source: Cancer Cell - June 29, 2019 Category: Cancer & Oncology Source Type: research

Overcoming Treatment Toxicity through Sequential Therapy
Publication date: 10 June 2019Source: Cancer Cell, Volume 35, Issue 6Author(s): Jan Benada, Bent Ejlertsen, Claus Storgaard SørensenCombined inhibitions of PARP and DNA damage checkpoint have the potential for high anti-cancer efficacy, but concurrent inhibitions have been hampered by intolerable side effects. In this issue of Cancer Cell, Fang and colleagues (Fang et al., 2019) propose that sequential inhibitions of PARP and DNA damage checkpoint considerably widen the therapeutic window. (Source: Cancer Cell)
Source: Cancer Cell - June 11, 2019 Category: Cancer & Oncology Source Type: research

The Worst from Both Worlds: cHCC-ICC
Publication date: 10 June 2019Source: Cancer Cell, Volume 35, Issue 6Author(s): Marco Seehawer, Luana D’Artista, Lars ZenderPrognosis of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma, a type of primary liver cancer comprising areas with HCC and ICC histopathology, is dismal, and it is unclear if such tumors develop clonally and how they should be treated. In this issue of Cancer Cell, Xue et al. (2019) provide answers to these questions. (Source: Cancer Cell)
Source: Cancer Cell - June 11, 2019 Category: Cancer & Oncology Source Type: research

Precision Oncology: Three Small Steps Forward
Publication date: 10 June 2019Source: Cancer Cell, Volume 35, Issue 6Author(s): Hannah C. Wise, David B. SolitOnly a subset of cancer patients currently benefit from personalized treatment approaches. Detection of actionable drug targets in cell-free DNA, more comprehensive molecular profiling integrating transcriptional analyses, and personalized combination regimens all hold promise in expanding the benefits of personalized oncology to larger numbers of cancer patients. (Source: Cancer Cell)
Source: Cancer Cell - June 11, 2019 Category: Cancer & Oncology Source Type: research

Fatty Acids Corrupt Neutrophils in Cancer
Publication date: 10 June 2019Source: Cancer Cell, Volume 35, Issue 6Author(s): Max D. Wellenstein, Karin E. de VisserUnderstanding how tumors escape from immune attack may offer novel therapeutic opportunities. Veglia et al. (2019) demonstrate in Nature that fatty acid transport protein 2 (FATP2) endows neutrophils with immunosuppressive capabilities that promote cancer growth. This receptor can be targeted to unleash anti-tumor immunity and to potentiate immune checkpoint blockade. (Source: Cancer Cell)
Source: Cancer Cell - June 11, 2019 Category: Cancer & Oncology Source Type: research

Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy
Publication date: 10 June 2019Source: Cancer Cell, Volume 35, Issue 6Author(s): Yong Fang, Daniel J. McGrail, Chaoyang Sun, Marilyne Labrie, Xiaohua Chen, Dong Zhang, Zhenlin Ju, Christopher P. Vellano, Yiling Lu, Yongsheng Li, Kang Jin Jeong, Zhiyong Ding, Jiyong Liang, Steven W. Wang, Hui Dai, Sanghoon Lee, Nidhi Sahni, Imelda Mercado-Uribe, Tae-beom Kim, Ken ChenSummaryWe demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage...
Source: Cancer Cell - June 11, 2019 Category: Cancer & Oncology Source Type: research

Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma
Publication date: 10 June 2019Source: Cancer Cell, Volume 35, Issue 6Author(s): Peiwen Chen, Di Zhao, Jun Li, Xin Liang, Jiexi Li, Andrew Chang, Verlene K. Henry, Zhengdao Lan, Denise J. Spring, Ganesh Rao, Y. Alan Wang, Ronald A. DePinhoSummaryHeterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX funct...
Source: Cancer Cell - June 11, 2019 Category: Cancer & Oncology Source Type: research