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Table of Contents

Breaking Insights

Reviews

Cancer Research Highlights

Controversy and Consensus

Genome and Epigenome

  • Genome and Epigenome
    BRD9 Is a Critical Regulator of Androgen Receptor Signaling and Prostate Cancer Progression
    Aktan Alpsoy, Sagar M. Utturkar, Benjamin C. Carter, Alisha Dhiman, Sandra E. Torregrosa-Allen, Melanie P. Currie, Bennett D. Elzey and Emily C. Dykhuizen
    Cancer Res February 15 2021 81 (4) 820-833; DOI:10.1158/0008-5472.CAN-20-1417

    Advanced prostate cancers resistant to androgen receptor antagonists are still susceptible to nontoxic BRD9 inhibitors, making them a promising alternative for halting AR signaling in progressed disease.

  • Genome and Epigenome
    Decitabine Induces Gene Derepression on Monosomic Chromosomes: In Vitro and In Vivo Effects in Adverse-Risk Cytogenetics AML
    Gabriele Greve, Julia Schüler, Björn A. Grüning, Bettina Berberich, Julia Stomper, Dennis Zimmer, Lea Gutenkunst, Ulrike Bönisch, Ruth Meier, Nadja Blagitko-Dorfs, Olga Grishina, Dietmar Pfeifer, Dieter Weichenhan, Christoph Plass and Michael Lübbert
    Cancer Res February 15 2021 81 (4) 834-846; DOI:10.1158/0008-5472.CAN-20-1430

    These findings unravel the molecular mechanism underlying the intriguing clinical activity of HMAs in AML/MDS patients with chromosome 7 deletions and other monosomal karyotypes.

  • Genome and Epigenome | AuthorChoice
    3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer
    Barrie Peck, Philip Bland, Ioanna Mavrommati, Gareth Muirhead, Hannah Cottom, Patty T. Wai, Sarah L. Maguire, Holly E. Barker, Eamonn Morrison, Divya Kriplani, Lu Yu, Amy Gibson, Giulia Falgari, Keith Brennan, Gillian Farnie, Richard Buus, Rebecca Marlow, Daniela Novo, Eleanor Knight, Naomi Guppy, Daniela Kolarevic, Snezana Susnjar, Natasa Medic Milijic, Kalnisha Naidoo, Patrycja Gazinska, Ioannis Roxanis, Sunil Pancholi, Lesley-Ann Martin, Erle M. Holgersen, Maggie C.U. Cheang, Farzana Noor, Sophie Postel-Vinay, Gerard Quinn, Simon McDade, Lukas Krasny, Paul Huang, Frances Daley, Fredrik Wallberg, Jyoti S. Choudhary, Syed Haider, Andrew N. Tutt and Rachael Natrajan
    Cancer Res February 15 2021 81 (4) 847-859; DOI:10.1158/0008-5472.CAN-20-1822

    This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.

Metabolism and Chemical Biology

Molecular Cell Biology

  • Molecular Cell Biology
    Cancer-Induced Muscle Wasting Requires p38β MAPK Activation of p300
    Thomas K. Sin, Guohua Zhang, Zicheng Zhang, James Z. Zhu, Yan Zuo, Jeffrey A. Frost, Min Li and Yi-Ping Li
    Cancer Res February 15 2021 81 (4) 885-897; DOI:10.1158/0008-5472.CAN-19-3219

    These findings demonstrate that prevention of p38β MAPK–mediated activation of p300 by the FDA-approved kinase inhibitor, nilotinib, ameliorates cancer cachexia, representing a potential therapeutic strategy against this syndrome.

  • Molecular Cell Biology
    A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression
    Dezuo Dong, Weimin Zhang, Wenchang Xiao, Qingnan Wu, Yiren Cao, Xiaohan Gao, Lijie Huang, Yan Wang, Jie Chen, Weihu Wang and Qimin Zhan
    Cancer Res February 15 2021 81 (4) 910-922; DOI:10.1158/0008-5472.CAN-20-0912

    These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC.

  • Molecular Cell Biology
    DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression
    Yinmin Gu, Shaoxi Niu, Yang Wang, Liqiang Duan, Yongbo Pan, Zhou Tong, Xu Zhang, Zhenyu Yang, Bo Peng, Xiaodong Wang, Xiaoqi Han, Yuxin Li, Tianyou Cheng, Yajuan Liu, Lina Shang, Tongfeng Liu, Xiwang Yang, Minxuan Sun, Siyuan Jiang, Chang Zhang, Ning Zhang, Qinong Ye and Shan Gao
    Cancer Res February 15 2021 81 (4) 923-934; DOI:10.1158/0008-5472.CAN-20-1619

    This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.

  • Molecular Cell Biology
    Robust p53 Stabilization Is Dispensable for Its Activation and Tumor Suppressor Function
    Ning Kon, Michael Churchill, Huan Li, Siddhartha Mukherjee, James J. Manfredi and Wei Gu
    Cancer Res February 15 2021 81 (4) 935-944; DOI:10.1158/0008-5472.CAN-20-1804

    Although robust p53 stabilization is critical for acute p53 responses such as DNA damage, this study underscores the important role of low basal p53 protein levels in p53 activation and tumor suppression.

  • Molecular Cell Biology
    GSK3β-Mediated Expression of CUG-Translated WT1 Is Critical for Tumor Progression
    Hisae Yoshitomi, Kun Y. Lee, Ke Yao, Seung Ho Shin, Tianshun Zhang, Qiushi Wang, Souren Paul, Eunmiri Roh, Joohyun Ryu, Hanyong Chen, Faisal Aziz, Abhijit Chakraborty, Ann M. Bode and Zigang Dong
    Cancer Res February 15 2021 81 (4) 945-955; DOI:10.1158/0008-5472.CAN-20-1880

    These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.

Tumor Biology and Immunology

  • Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function
    Tumor Biology and Immunology
    Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function
    Linnéa La Fleur, Johan Botling, Fei He, Catarina Pelicano, Chikai Zhou, Chenfei He, Giorgia Palano, Artur Mezheyeuski, Patrick Micke, Jeffrey V. Ravetch, Mikael C. I. Karlsson and Dhifaf Sarhan
    Cancer Res February 15 2021 81 (4) 956-967; DOI:10.1158/0008-5472.CAN-20-1885

    This study defines tumor-derived IL37 and the macrophage scavenger receptor MARCO as potential therapeutic targets to remodel the immune-suppressive microenvironment in patients with lung cancer.

  • Tumor Biology and Immunology
    Pharmacologic Activation of LXR Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment
    José M. Carbó, Theresa E. León, Joan Font-Díaz, Juan Vladimir De la Rosa, Antonio Castrillo, Felix R. Picard, Daniel Staudenraus, Magdalena Huber, Lídia Cedó, Joan Carles Escolà-Gil, Lucía Campos, Latifa Bakiri, Erwin F. Wagner, Carme Caelles, Thomas Stratmann, Jo A. Van Ginderachter and Annabel F. Valledor
    Cancer Res February 15 2021 81 (4) 968-985; DOI:10.1158/0008-5472.CAN-19-3360

    This study reveals unrecognized roles of LXR in the transcriptional control of the tumor microenvironment and suggests use of a synthetic LXR agonist as a novel therapeutic strategy to stimulate antitumor activity.

  • Tumor Biology and Immunology
    ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly
    Shayi Wu, Miao Chen, Jiao Huang, Feifei Zhang, Zhaojie Lv, Yongxu Jia, Yu-Zhu Cui, Liang-Zhan Sun, Ying Wang, Ying Tang, Krista R. Verhoeft, Yan Li, Yanru Qin, Xiang Lin, Xin-Yuan Guan and Ka-On Lam
    Cancer Res February 15 2021 81 (4) 986-1000; DOI:10.1158/0008-5472.CAN-20-0049

    These findings describe the critical role of ORAI2 in gastric cancer cell migration and tumor metastasis and uncover the translational potential to advance drug discovery along the ORAI2 signaling pathway.

  • Tumor Biology and Immunology
    Newly Identified Members of FGFR1 Splice Variants Engage in Cross-talk with AXL/AKT Axis in Salivary Adenoid Cystic Carcinoma
    Joseph O. Humtsoe, Hyun-Su Kim, Brandon Leonard, Shizhang Ling, Bhumsuk Keam, Luigi Marchionni, Bahman Afsari, Michael Considine, Alexander V. Favorov, Elana J. Fertig, Hyunseok Kang and Patrick K. Ha
    Cancer Res February 15 2021 81 (4) 1001-1013; DOI:10.1158/0008-5472.CAN-20-1780

    This study identifies several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor suggestive of a potential resistance mechanism in ACC.

  • Tumor Biology and Immunology
    Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis
    Minhong Shen, Shanshan Xie, Michelle Rowicki, Sven Michel, Yong Wei, Xiang Hang, Liling Wan, Xin Lu, Min Yuan, John F. Jin, Frank Jaschinski, Tianhua Zhou, Richard Klar and Yibin Kang
    Cancer Res February 15 2021 81 (4) 1014-1025; DOI:10.1158/0008-5472.CAN-20-1876

    This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.

  • Tumor Biology and Immunology
    KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer
    Lin Gao, Wenbo Zhang, Jing Zhang, Junmei Liu, Feifei Sun, Hui Liu, Jing Hu, Xin Wang, Xueli Wang, Peng Su, Shouzhen Chen, Sifeng Qu, Benkang Shi, Xueting Xiong, Weiwen Chen, Xuesen Dong and Bo Han
    Cancer Res February 15 2021 81 (4) 1026-1039; DOI:10.1158/0008-5472.CAN-20-1965

    These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlight cotargeting KIF15 and AR as a therapeutic strategy for these tumors.

  • Tumor Biology and Immunology
    Cancer Cell Fitness Is Dynamic
    Luana S. Lenz, Juliano L. Faccioni, Paula A. Bracco, Jephesson A.F. Santos, Luiza C. Pereira, Julieti H. Buss, Mauricio T. Tamborindeguy, Daphne Torgo, Thayana Monteiro, Giovana B. Mantovani, Carolina N. Santo, Julia C. Marcolin, Eloisa Dalsin, Alvaro Vigo, Sidia M. Callegari-Jacques, Andrew O. Silva, Giovana R. Onzi, Karine R. Begnini and Guido Lenz
    Cancer Res February 15 2021 81 (4) 1040-1051; DOI:10.1158/0008-5472.CAN-20-2488

    Cancer cell fitness is dynamic over the course of the formation of colonies. This dynamic behavior is mediated by asymmetric mitosis, ERK activity, cell-cycle duration, and DNA repair capacity in the absence or presence of a drug.

Translational Science

  • Translational Science | AuthorChoice
    E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling
    Kazuhiko Yamada, Yusaku Hori, Satoshi Inoue, Yuji Yamamoto, Kentaro Iso, Hiroshi Kamiyama, Atsumi Yamaguchi, Takayuki Kimura, Mai Uesugi, Junichi Ito, Masahiro Matsuki, Kazutaka Nakamoto, Hitoshi Harada, Naoki Yoneda, Atsushi Takemura, Ikuo Kushida, Naomi Wakayama, Kenji Kubara, Yu Kato, Taro Semba, Akira Yokoi, Masayuki Matsukura, Takenao Odagami, Masao Iwata, Akihiko Tsuruoka, Toshimitsu Uenaka, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa, Yasuhiro Funahashi and Yoichi Ozawa
    Cancer Res February 15 2021 81 (4) 1052-1062; DOI:10.1158/0008-5472.CAN-20-0782

    These findings demonstrate that the novel anticancer agent E7386, modulates Wnt/β-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.

  • Translational Science
    ATG5-Dependent Autophagy Uncouples T-cell Proliferative and Effector Functions and Separates Graft-versus-Host Disease from Graft-versus-Leukemia
    Katherine Oravecz-Wilson, Corinne Rossi, Cynthia Zajac, Yaping Sun, Lu Li, Thomas Decoville, Hideaki Fujiwara, Stephanie Kim, Daniel Peltier and Pavan Reddy
    Cancer Res February 15 2021 81 (4) 1063-1075; DOI:10.1158/0008-5472.CAN-20-1346

    These findings demonstrate that induction of autophagy in donor T-cell promotes GVHD, while inhibition of T-cell autophagy mitigates GVHD without substantial loss of GVL responses.

  • Translational Science
    A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models
    Shaun D. Fontaine, Gary W. Ashley, Peter J. Houghton, Raushan T. Kurmasheva, Morgan Diolaiti, Alan Ashworth, Cody J. Peer, Ryan Nguyen, William D. Figg Sr., Denis R. Beckford-Vera and Daniel V. Santi
    Cancer Res February 15 2021 81 (4) 1076-1086; DOI:10.1158/0008-5472.CAN-20-1741

    These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.

  • Translational Science | AuthorChoice
    JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer
    Alec Paschalis, Jonathan Welti, Antje J. Neeb, Wei Yuan, Ines Figueiredo, Rita Pereira, Ana Ferreira, Ruth Riisnaes, Daniel Nava Rodrigues, Juan M. Jiménez-Vacas, Soojin Kim, Takuma Uo, Patrizio Di Micco, Anthony Tumber, Md. Saiful Islam, Marc A. Moesser, Martine Abboud, Akane Kawamura, Bora Gurel, Rossitza Christova, Veronica S. Gil, Lorenzo Buroni, Mateus Crespo, Susana Miranda, Maryou B. Lambros, Suzanne Carreira, Nina Tunariu, Andrea Alimonti; , SU2C/PCF International Prostate Cancer Dream Team, Bissan Al-Lazikani, Christopher J. Schofield, Stephen R. Plymate, Adam Sharp and Johann S. de Bono
    Cancer Res February 15 2021 81 (4) 1087-1100; DOI:10.1158/0008-5472.CAN-20-1807

    This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.

  • Translational Science
    Identifying Clear Cell Renal Cell Carcinoma Coexpression Networks Associated with Opioid Signaling and Survival
    Joseph R. Scarpa, Renzo G. DiNatale, Roy Mano, Andrew W. Silagy, Fengshen Kuo, Takeshi Irie, Patrick J. McCormick, Gregory W. Fischer, A. Ari Hakimi and Joshua S. Mincer
    Cancer Res February 15 2021 81 (4) 1101-1110; DOI:10.1158/0008-5472.CAN-20-1852

    This study suggests a possible molecular mechanism for opioid effects on cancer outcomes generally, with implications for personalization of analgesic regimens.

  • Translational Science | AuthorChoice
    MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells
    Masayuki Hagiwara, Yota Yasumizu, Nami Yamashita, Hasan Rajabi, Atsushi Fushimi, Mark D. Long, Wei Li, Atrayee Bhattacharya, Rehan Ahmad, Mototsugu Oya, Song Liu and Donald Kufe
    Cancer Res February 15 2021 81 (4) 1111-1122; DOI:10.1158/0008-5472.CAN-20-2588

    These findings show that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.

Convergence and Technologies

  • Optimal Timing for Cancer Screening and Adaptive Surveillance Using Mathematical Modeling
    Convergence and Technologies
    Optimal Timing for Cancer Screening and Adaptive Surveillance Using Mathematical Modeling
    Kit Curtius, Anup Dewanji, William D. Hazelton, Joel H. Rubenstein and Georg E. Luebeck
    Cancer Res February 15 2021 81 (4) 1123-1134; DOI:10.1158/0008-5472.CAN-20-0335

    This study demonstrates how mathematical modeling of cancer evolution can be used to optimize screening regimes, with the added potential to improve surveillance regimes.

  • Convergence and Technologies
    Turnover Modulates the Need for a Cost of Resistance in Adaptive Therapy
    Maximilian A.R. Strobl, Jeffrey West, Yannick Viossat, Mehdi Damaghi, Mark Robertson-Tessi, Joel S. Brown, Robert A. Gatenby, Philip K. Maini and Alexander R.A. Anderson
    Cancer Res February 15 2021 81 (4) 1135-1147; DOI:10.1158/0008-5472.CAN-20-0806

    Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy.

Population and Prevention Science

  • Population and Prevention Science
    Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer
    Zhiwei Liu, Andriy Derkach, Kelly J. Yu, Meredith Yeager, Yu-Sun Chang, Chien-Jen Chen, Ulf Gyllensten, Qing Lan, Mei-Hsuan Lee, James D. McKay, Nathaniel Rothman, Hwai-I Yang, Allan Hildesheim and Ruth M. Pfeiffer
    Cancer Res February 15 2021 81 (4) 1148-1152; DOI:10.1158/0008-5472.CAN-20-2292

    GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.

  • Population and Prevention Science | AuthorChoice
    Time-Dependent Effects of Oral Contraceptive Use on Breast, Ovarian, and Endometrial Cancers
    Torgny Karlsson, Therese Johansson, Julia Höglund, Weronica E. Ek and Åsa Johansson
    Cancer Res February 15 2021 81 (4) 1153-1162; DOI:10.1158/0008-5472.CAN-20-2476

    These results enable women and physicians to make more informed decisions considering oral contraceptive use, thus constituting an important step towards personalized medicine.

  • Population and Prevention Science
    Racial/Ethnic Disparities in All-Cause Mortality among Patients Diagnosed with Triple-Negative Breast Cancer
    Fei Wang, Wei Zheng, Christina E. Bailey, Ingrid A. Mayer, Jennifer A. Pietenpol and Xiao-Ou Shu
    Cancer Res February 15 2021 81 (4) 1163-1170; DOI:10.1158/0008-5472.CAN-20-3094

    These findings highlight the need for equal healthcare to mitigate the black–white disparity and for investigations of contributors beyond healthcare for lower mortality among Asians and Hispanics.

Resource Reports

  • Resource Reports
    Interactive Classification of Whole-Slide Imaging Data for Cancer Researchers
    Sanghoon Lee, Mohamed Amgad, Pooya Mobadersany, Matt McCormick, Brian P. Pollack, Habiba Elfandy, Hagar Hussein, David A. Gutman and Lee A.D. Cooper
    Cancer Res February 15 2021 81 (4) 1171-1177; DOI:10.1158/0008-5472.CAN-20-0668

    An interactive machine learning tool for analyzing digital pathology images enables cancer researchers to apply this tool to measure histologic patterns for clinical and basic science studies.

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