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Table of Contents

Breaking Insights

Review

  • Review | AuthorChoice
    Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers
    Adam J. Wolpaw, Richard Bayliss, Gabriele Büchel, Chi V. Dang, Martin Eilers, W. Clay Gustafson, Gwenn H. Hansen, Natalia Jura, Stefan Knapp, Mark A. Lemmon, David Levens, John M. Maris, Ronen Marmorstein, Steven J. Metallo, Julie R. Park, Linda Z. Penn, Michael Rape, Martine F. Roussel, Kevan M. Shokat, William P. Tansey, Kliment A. Verba, Seychelle M. Vos, William A. Weiss, Elmar Wolf and Yaël P. Mossé
    Cancer Res April 1 2021 81 (7) 1627-1632; DOI:10.1158/0008-5472.CAN-20-3108

Cancer Research Highlights

Genome and Epigenome

  • Cancer-Associated Fibroblasts Promote Aggressive Gastric Cancer Phenotypes via Heat Shock Factor 1–Mediated Secretion of Extracellular Vesicles
    Genome and Epigenome
    Cancer-Associated Fibroblasts Promote Aggressive Gastric Cancer Phenotypes via Heat Shock Factor 1–Mediated Secretion of Extracellular Vesicles
    Nil Grunberg, Meirav Pevsner-Fischer, Tal Goshen-Lago, Judith Diment, Yaniv Stein, Hagar Lavon, Shimrit Mayer, Oshrat Levi-Galibov, Gil Friedman, Yifat Ofir-Birin, Li-Jyun Syu, Cristina Migliore, Eyal Shimoni, Salomon M. Stemmer, Baruch Brenner, Andrzej A. Dlugosz, David Lyden, Neta Regev-Rudzki, Irit Ben-Aharon and Ruth Scherz-Shouval
    Cancer Res April 1 2021 81 (7) 1639-1653; DOI:10.1158/0008-5472.CAN-20-2756

    This study shows how HSF1 regulates a stromal transcriptional program associated with aggressive gastric cancer and identifies multiple proteins within this program as candidates for therapeutic intervention.

  • Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer
    Genome and Epigenome
    Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer
    Yoshihiko Tasaki, Miho Suzuki, Keisuke Katsushima, Keiko Shinjo, Kenta Iijima, Yoshiteru Murofushi, Aya Naiki-Ito, Kazuki Hayashi, Chenjie Qiu, Akiko Takahashi, Yoko Tanaka, Tokuichi Kawaguchi, Minoru Sugawara, Tomoya Kataoka, Mitsuru Naito, Kanjiro Miyata, Kazunori Kataoka, Tetsuo Noda, Wentao Gao, Hiromi Kataoka, Satoru Takahashi, Kazunori Kimura and Yutaka Kondo
    Cancer Res April 1 2021 81 (7) 1654-1666; DOI:10.1158/0008-5472.CAN-20-3021

    Targeting TUG1 coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in TUG1-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment.

  • Genome and Epigenome
    Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response
    Ping Zhang, Isaac Kitchen-Smith, Lingyun Xiong, Giovanni Stracquadanio, Katherine Brown, Philipp H. Richter, Marsha D. Wallace, Elisabeth Bond, Natasha Sahgal, Samantha Moore, Svanhild Nornes, Sarah De Val, Mirvat Surakhy, David Sims, Xuting Wang, Douglas A. Bell, Jorge Zeron-Medina, Yanyan Jiang, Anderson J. Ryan, Joanna L. Selfe, Janet Shipley, Siddhartha Kar, Paul D. Pharoah, Chey Loveday, Rick Jansen, Lukasz F. Grochola, Claire Palles, Andrew Protheroe, Val Millar, Daniel V. Ebner, Meghana Pagadala, Sarah P. Blagden, Timothy S. Maughan, Enric Domingo, Ian Tomlinson, Clare Turnbull, Hannah Carter and Gareth L. Bond
    Cancer Res April 1 2021 81 (7) 1667-1680; DOI:10.1158/0008-5472.CAN-20-0177

    These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.

  • Genome and Epigenome
    Multiomics Characterization of Low-Grade Serous Ovarian Carcinoma Identifies Potential Biomarkers of MEK Inhibitor Sensitivity and Therapeutic Vulnerability
    Raunak Shrestha, Marta Llaurado Fernandez, Amy Dawson, Joshua Hoenisch, Stanislav Volik, Yen-Yi Lin, Shawn Anderson, Hannah Kim, Anne M. Haegert, Shane Colborne, Nelson K.Y. Wong, Brian McConeghy, Robert H. Bell, Sonal Brahmbhatt, Cheng-Han Lee, Gabriel E. DiMattia, Stephane Le Bihan, Gregg B. Morin, Colin C. Collins and Mark S. Carey
    Cancer Res April 1 2021 81 (7) 1681-1694; DOI:10.1158/0008-5472.CAN-20-2222

    These findings highlight the utility of global multiomics to characterize LGSOC cell lines as research models, to determine biomarkers of MEKi resistance, and to identify potential novel therapeutic targets.

  • Genome and Epigenome
    A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility
    Nima C. Emami, Taylor B. Cavazos, Sara R. Rashkin, Clinton L. Cario, Rebecca E. Graff, Caroline G. Tai, Joel A. Mefford, Linda Kachuri, Eunice Wan, Simon Wong, David Aaronson, Joseph Presti, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Chun R. Chao, Nirupa R. Ghai, Eric Jorgenson, Lori C. Sakoda, Mark N. Kvale, Pui-Yan Kwok, Catherine Schaefer, Neil Risch, Thomas J. Hoffmann, Stephen K. Van Den Eeden and John S. Witte
    Cancer Res April 1 2021 81 (7) 1695-1703; DOI:10.1158/0008-5472.CAN-20-2635

    This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.

Metabolism and Chemical Biology

  • Metabolism and Chemical Biology
    ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer
    Margaret M. Centenera, Julia S. Scott, Jelle Machiels, Zeyad D. Nassar, Deanna C. Miller, Irene Zinonos, Jonas Dehairs, Ingrid J.G. Burvenich, Giorgia Zadra, Paolo M. Chetta, Clyde Bango, Emma Evergren, Natalie K. Ryan, Joanna L. Gillis, Chui Yan Mah, Terence Tieu, Adrienne R. Hanson, Ryan Carelli, Katarzyna Bloch, Vasilios Panagopoulos, Etienne Waelkens, Rita Derua, Elizabeth D. Williams, Andreas Evdokiou, Anna Cifuentes-Rius, Nicolas H. Voelcker, Ian G. Mills, Wayne D. Tilley, Andrew M. Scott, Massimo Loda, Luke A. Selth, Johannes V. Swinnen and Lisa M. Butler
    Cancer Res April 1 2021 81 (7) 1704-1718; DOI:10.1158/0008-5472.CAN-20-2511

    This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.

Molecular Cell Biology

  • Molecular Cell Biology
    CKAP2L Promotes Non–Small Cell Lung Cancer Progression through Regulation of Transcription Elongation
    Tiziana Monteverde, Sudhakar Sahoo, Manuela La Montagna, Peter Magee, Lei Shi, Dave Lee, Robert Sellers, Alexander R. Baker, Hui Sun Leong, Matteo Fassan and Michela Garofalo
    Cancer Res April 1 2021 81 (7) 1719-1731; DOI:10.1158/0008-5472.CAN-20-1968

    These findings demonstrate the oncogenic function of CKAP2L through regulation of transcription elongation and suggest that targeting CKAP2L could enhance therapeutic response in patients with NSCLC.

  • Molecular Cell Biology
    Glia-Selective Deletion of Complement C1q Prevents Radiation-Induced Cognitive Deficits and Neuroinflammation
    Mineh Markarian, Robert P. Krattli Jr, Jabra D. Baddour, Leila Alikhani, Erich Giedzinski, Manal T. Usmani, Anshu Agrawal, Janet E. Baulch, Andrea J. Tenner and Munjal M. Acharya
    Cancer Res April 1 2021 81 (7) 1732-1744; DOI:10.1158/0008-5472.CAN-20-2565

    Clinically-relevant radiotherapy induces aberrant complement activation, leading to brain injury. Microglia-selective genetic deletion of CNS complement C1q ameliorates radiation-induced cognitive impairments, synaptic loss, and neuroinflammation, highlighting the potential for C1q as a novel therapeutic target.

  • Molecular Cell Biology
    RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer
    Frank Arnold, Johann Gout, Heike Wiese, Stephanie E. Weissinger, Elodie Roger, Lukas Perkhofer, Karolin Walter, Jeanette Scheible, Caterina Prelli Bozzo, André Lechel, Thomas J. Ettrich, Ninel Azoitei, Li Hao, Axel Fürstberger, Ewa K. Kaminska, Konstantin M.J. Sparrer, Volker Rasche, Sebastian Wiese, Hans A. Kestler, Peter Möller, Thomas Seufferlein, Pierre-Olivier Frappart and Alexander Kleger
    Cancer Res April 1 2021 81 (7) 1758-1774; DOI:10.1158/0008-5472.CAN-20-2633

    These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.

Tumor Biology and Immunology

  • Tumor Biology and Immunology
    Cooperative Targeting of Immunotherapy-Resistant Melanoma and Lung Cancer by an AXL-Targeting Antibody–Drug Conjugate and Immune Checkpoint Blockade
    Julia Boshuizen, Nora Pencheva, Oscar Krijgsman, Daniela D'Empaire Altimari, Patricia Garrido Castro, Beaunelle de Bruijn, Maarten A. Ligtenberg, Elke Gresnigt-Van den Heuvel, David W. Vredevoogd, Ji-Ying Song, Nils Visser, Georgi Apriamashvili, Maarten L. Janmaat, Theo S. Plantinga, Patrick Franken, Mischa Houtkamp, Andreas Lingnau, Maria Jure-Kunkel and Daniel S. Peeper
    Cancer Res April 1 2021 81 (7) 1775-1787; DOI:10.1158/0008-5472.CAN-20-0434

    These findings show that targeting AXL-positive tumor fractions with an antibody–drug conjugate enhances anti-tumor immunity in several humanized tumor models of melanoma and lung cancer.

  • Tumor Biology and Immunology
    Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T-cell Engagers Generates Antitumor Immunity While Avoiding Anergy
    Shalu Sharma Kharkwal, Christopher T. Johndrow, Natacha Veerapen, Himanshu Kharkwal, Noemi A. Saavedra-Avila, Leandro J. Carreño, Samantha Rothberg, Jinghang Zhang, Scott J. Garforth, Peter J. Jervis, Lianjun Zhang, Alena Donda, Amareeta K. Besra, Liam R. Cox, Steven C. Almo, Alan Howell, Elizabeth E. Evans, Maurice Zauderer, Gurdyal S. Besra and Steven A. Porcelli
    Cancer Res April 1 2021 81 (7) 1788-1801; DOI:10.1158/0008-5472.CAN-20-2219

    Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells.

  • Tumor Biology and Immunology
    Pan-Cancer Analysis of Ligand–Receptor Cross-talk in the Tumor Microenvironment
    Umesh Ghoshdastider, Neha Rohatgi, Marjan Mojtabavi Naeini, Probhonjon Baruah, Egor Revkov, Yu Amanda Guo, Simone Rizzetto, Angeline M.L. Wong, Sundar Solai, Tin T. Nguyen, Joe Poh Sheng Yeong, Jabed Iqbal, Puay Hoon Tan, Balram Chowbay, Ramanuj Dasgupta and Anders J. Skanderup
    Cancer Res April 1 2021 81 (7) 1802-1812; DOI:10.1158/0008-5472.CAN-20-2352

    This study provides deconvoluted bulk tumor transcriptomes across multiple cancer types to infer cross-talk in the tumor microenvironment.

  • Tumor Biology and Immunology | AuthorChoice
    Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis
    Mingrui Zhu, Yi Huang, Matthew E. Bender, Luc Girard, Rahul Kollipara, Buse Eglenen-Polat, Yujiro Naito, Trisha K. Savage, Kenneth E. Huffman, Shohei Koyama, Atsushi Kumanogoh, John D. Minna, Jane E. Johnson and Esra A. Akbay
    Cancer Res April 1 2021 81 (7) 1813-1826; DOI:10.1158/0008-5472.CAN-20-2808

    This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.

  • Tumor Biology and Immunology
    Survivin Expression Is Differentially Regulated by a Selective Cross-talk between RBM38 and miRNAs let-7b or miR-203a
    Christopher A. Lucchesi, Jin Zhang, Buyong Ma, Ruth Nussinov and Xinbin Chen
    Cancer Res April 1 2021 81 (7) 1827-1839; DOI:10.1158/0008-5472.CAN-20-3157

    These findings show that RBM38 exerts opposing effects on survivin expression via two miRNAs, and disruption of the RBM38–AGO2 complex by an eight-amino acid peptide sensitizes tumor spheroids to survivin inhibitor YM155.

Convergence and Technologies

Translational Science

  • Translational Science | AuthorChoice
    The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress–Mediated Apoptosis in Pancreatic Cancer
    Soma Samanta, Suhui Yang, Bikash Debnath, Ding Xue, Yuting Kuang, Kavya Ramkumar, Amy S. Lee, Mats Ljungman and Nouri Neamati
    Cancer Res April 1 2021 81 (7) 1883-1895; DOI:10.1158/0008-5472.CAN-20-1540

    This study identifies a novel ER stress inducer that binds GRP78 and inhibits pancreatic cancer cell growth in vitro and in vivo, demonstrating its potential as a therapeutic agent for pancreatic cancer.

  • Translational Science
    MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis
    Konstantinos V. Floros, JinYang Cai, Sheeba Jacob, Richard Kurupi, Carter K. Fairchild, Mayuri Shende, Colin M. Coon, Krista M. Powell, Benjamin R. Belvin, Bin Hu, Madhavi Puchalapalli, Sivapriya Ramamoorthy, Kimberly Swift, Janina P. Lewis, Mikhail G. Dozmorov, John Glod, Jennifer E. Koblinski, Sosipatros A. Boikos and Anthony C. Faber
    Cancer Res April 1 2021 81 (7) 1896-1908; DOI:10.1158/0008-5472.CAN-20-1641

    The study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.

  • Translational Science
    Delta-Like Ligand–Notch1 Signaling Is Selectively Modulated by HPV16 E6 to Promote Squamous Cell Proliferation and Correlates with Cervical Cancer Prognosis
    Maryam Khelil, Heather Griffin, Maaike C.G. Bleeker, Renske D.M. Steenbergen, Ke Zheng, Taylor Saunders-Wood, Sanne Samuels, Jossie Rotman, Wim Vos, Brendy E. van den Akker, Renée X. de Menezes, Gemma G. Kenter, John Doorbar and Ekaterina S. Jordanova
    Cancer Res April 1 2021 81 (7) 1909-1921; DOI:10.1158/0008-5472.CAN-20-1996

    This study investigates cervical cancer cell-of-origin populations and describes a DLL-Notch1 phenotype that is associated with disease prognosis and that might help identify cells that are susceptible to HPV-induced carcinogenesis.

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