BREAKING INSIGHTS 5159 ATMIN Is a Tumor Suppressor Gene in Lung Adenocarcinoma 5129 Highlights from Recent Cancer Literature Hanna Foster, E. Josue Ruiz, Christopher Moore, Gordon W.H. Stamp, Emma L. Nye, Ningning Li, Yihang Pan, Yulong He, Julian Downward, and Axel Behrens REVIEWS Significance: These findings identify ATMIN as a tumor suppressor in LUAD; fragility at chr16q23 correlates with 5131 Roles and Regulation of Long Noncoding RNAs loss of ATMIN in human LUAD and deletion of Atmin in Hepatocellular Carcinoma increases tumor burden in a LUAD mouse model. Lee Jin Lim, Samuel Y.S. Wong, Feiyang Huang, Sheng Lim, Samuel S. Chong, London Lucien Ooi, Oi Lian Kon, and Caroline G. Lee GENOME AND EPIGENOME

5140 Value of Collaboration among Multi-Domain 5167 Identification of Coding and Long Noncoding Experts in Analysis of High-Throughput RNAs Differentially Expressed in Tumors and Genomics Data Preferentially Expressed in Healthy Tissues Daoud Meerzaman and Barbara K. Dunn Juan P. Unfried, Guillermo Serrano, Beatriz Suarez,

Comparing healthy tissues and tumor samples reveals that the testis and brain are the major tissues that preferentially express relevant RNAs upregulated in tumors. © 2019 American Association for Cancer Research Paloma Sangro, Valeria Ferretti, Celia Prior, Loreto Boix, Jordi Bruix, Bruno Sangro, Víctor Segura, and Puri Fortes CANCER RESEARCH HIGHLIGHTS Significance: Comprehensive analysis of coding and noncoding genes expressed in different tumors and normal 5146 Targeting Semaphorin 4D in Cancer: A Look from tissues, which should be taken into account to predict side Different Perspectives effects from potential coding and noncoding gene-targeting Luca Tamagnone and Giulia Franzolin therapies. See related article, p. 5328 5181 Banding Together: A Systematic Comparison of 5149 Stearoyl CoA Desaturase Regulates Ferroptosis in The Cancer Genome Atlas and the Mitelman Ovarian Cancer Offering New Therapeutic Databases Perspectives Connor Denomy, Samuel Germain, Bjorn Haave, Michele Carbone and Gerry Melino Frederick S. Vizeacoumar, Andrew Freywald, Beth A. Weaver, and Franco J. Vizeacoumar See related article, p. 5355 Significance: A novel in silico approach compares cytogenetic data between the Mitelman database and TCGA, PRIORITY REPORT highlighting the advantages and limitations of both datasets.

5151 miR-221 Targets QKI to Enhance the Tumorigenic METABOLISM AND CHEMICAL BIOLOGY Capacity of Human Colorectal Cancer Stem Cells Junko Mukohyama, Taichi Isobe, Qingjiang Hu, 5191 Targeting Myeloperoxidase Disrupts Takanori Hayashi, Takashi Watanabe, Masao Maeda, Mitochondrial Redox Balance and Overcomes Hisano Yanagi, Xin Qian, Kimihiro Yamashita, Cytarabine Resistance in Human Acute Myeloid Hironobu Minami, Koshi Mimori, Debashis Sahoo, Leukemia Yoshihiro Kakeji, Akira Suzuki, Piero Dalerba, and Mohsen Hosseini, Hamid Reza Rezvani, Nesrine Aroua, Yohei Shimono Claudie Bosc, Thomas Farge, Estelle Saland, Significance: These findings uncover molecular Veronique Guyonnet-Duperat, Sonia Zaghdoudi, mechanisms underlying the maintenance of cancer stem Latifa Jarrou, Clement Larrue, Marie Sabatier, cell properties in colon cancer. Pierre Luc Mouchel, Mathilde Gotanegre, Marc Piechaczyk, Guillaume Bossis, Christian Recher, and Jean-Emmanuel Sarry Significance: These findings demonstrate the role of myeloperoxidase in the regulation of ROS levels and sensitivity of AML cells to cytarabine, an essential chemotherapeutic backbone in the therapy of AML.

MOLECULAR CELL BIOLOGY 5272 Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA 5204 SF3B2-Mediated RNA Splicing Drives Human Polymerase Transcriptional Activity Jesse J. Balic, Daniel J. Garama, Mohamed I. Saad, General RNA splicing SF3B2 complex-mediated alternative RNA splicing Prostate Cancer Progression U2 U2 snRNA

3’ 3’ 5’ 3’ splice site 5’ SF3B7 5’ A U2AF2 AGA Exon ? SF3B6(p14) SF3B4 SF3B1 SF3B4 SF3B1 SF3B5 Liang Yu, Alison C. West, Alice J. West, Thaleia Livis, SF3B2 SF3B3 SF3B2 SF3B3 SF3A3 SF3B2 complex SF3A3 SF3A1 SF3A1 SF3b complex AR pre-mRNA Norihiko Kawamura, Keisuke Nimura, Kotaro Saga, CE3

AR-V7 mRNA AR mRNA CE3

Drive malignancy While the SF3b complex is critical for general RNA splicing, SF3B2 promotes inclusion of the target exon through recognizing a speciﬁc RNA motif. Prithi S. Bhathal, Daniel J. Gough, and Brendan J. Jenkins © 2019 American Association for Cancer Research Airi Ishibashi, Koji Kitamura, Hiromichi Nagano, Yusuke Yoshikawa, Kyoso Ishida, Norio Nonomura, Significance: These findings reveal a new transcriptional Mitsuhiro Arisawa, Jun Luo, and Yasufumi Kaneda role and mandatory requirement for constitutive STAT3 Significance: RNA splicing factor SF3B2 is essential for the serine phosphorylation in gastric cancer. generation of an androgen receptor (AR) variant that renders prostate cancer cells resistant to AR-targeting 5288 SRSF3-Regulated RNA Alternative Splicing therapy. Promotes Glioblastoma Tumorigenicity by Affecting Multiple Cellular Processes Xiao Song, Xuechao Wan, Tianzhi Huang, Chang Zeng, 5218 Mitochondrial NIX Promotes Tumor Survival Namratha Sastry, Bingli Wu, C. David James, in the Hypoxic Niche of Glioblastoma Craig Horbinski, Ichiro Nakano, Wei Zhang, Bo Hu, Jinkyu Jung, Ying Zhang, Orieta Celiku, Wei Zhang, and Shi-Yuan Cheng Hua Song, Brian J. Williams, Amber J. Giles, Jeremy N. Rich, Roger Abounader, Mark R. Gilbert, and Significance: SRSF3 is a significant regulator of Deric M. Park glioma-associated alternative splicing, implicating SRSF3 as an oncogenic factor that contributes to the Significance: NIX-mediated mitophagy regulates tumor tumor biology of GBM. survival in the hypoxic niche of glioblastoma microenvironment, providing a potential therapeutic target for glioblastoma. TUMOR BIOLOGY AND IMMUNOLOGY 5233 Phosphorylation of HSF1 by PIM2 Induces 5302 PD-L1 Expression and Promotes Tumor The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response

Growth in Breast Cancer High dose

Moderate dose Just Right Lymphodepleting Tingting Yang, Chune Ren, Chao Lu, Pengyun Qiao, chemotherapy

Low dose

Tolerized cells Effector T cells Regulatory T cells Tumor cells Derek S. Park, Mark Robertson-Tessi, Kimberly A. Luddy, Moderate chemotherapy dosing can lead to optimal outcomes through balancing cytotoxicity with preserving immune state to support a long-term antitumor T-cell response. Xue Han, Li Wang, Dan Wang, Shijun Lv, Yonghong Sun, © 2019 American Association for Cancer Research Philip K. Maini, Michael B. Bonsall, Robert A. Gatenby, and Zhenhai Yu and Alexander R.A. Anderson Significance: These findings identify heat shock Significance: To maximize the synergy between transcription factor 1 as a new substrate for PIM2 kinase chemotherapy and antitumor immune response, and establish its role in breast tumor progression. lymphodepleting therapy must be balanced in a "Goldilocks Window" of optimal dosing. 5245 CDK4 Regulates Lysosomal Function and mTORC1 Activation to Promote Cancer Cell 5316 Prolactin Promotes Fibrosis and Pancreatic Survival Cancer Progression Laia Martínez-Carreres, Julien Puyal, Manuj Tandon, Gina M. Coudriet, Angela Criscimanna, Lucía C. Leal-Esteban, Meritxell Orpinell, Mairobys Socorro, Mouhanned Eliliwi, Aatur D. Singhi, Judit Castillo-Armengol, Albert Giralt, Oleksandr Dergai, Zobeida Cruz-Monserrate, Peter Bailey, Michael T. Lotze, Catherine Moret, Valentin Barquissau, Anita Nasrallah, Herbert Zeh, Jing Hu, Vincent Goffin, George K. Gittes, Angelique Pabois, Lianjun Zhang, Pedro Romero, Andrew V. Biankin, and Farzad Esni Isabel C. Lopez-Mejia, and Lluis Fajas Significance: Prolactin is a key factor in the cross-talk Significance: These findings uncover a novel function of between the stroma and neoplastic epithelium, functioning to CDK4 in lysosomal biology, which promotes cancer promote fibrosis and PDAC progression. progression by activating mTORC1; targeting this function offers a new therapeutic strategy for cancer treatment. 5328 Antitumor Effects of Anti-Semaphorin 4D Antibody Unravel a Novel Proinvasive

Binding of the vascular-targeting agent anti-Sema4D to Sema4D on macrophages promotes a malignant phenotype via SDF1/CXCR4 signaling. 5260 ZBTB7A Mediates the Transcriptional Repression © 2019 American Association for Cancer Research Mechanism of Vascular-Targeting Agents Activity of the Androgen Receptor in Prostate Iratxe Zuazo-Gaztelu, Marta Paez-Ribes, Patricia Carrasco, Cancer Laura Martín, Adriana Soler, Mar Martínez-Lozano, Dong Han, Sujun Chen, Wanting Han, Shuai Gao, Roser Pons, Judith Llena, Luis Palomero, Jude N. Owiredu, Muqing Li, Steven P. Balk, Mariona Graupera, and Oriol Casanovas Housheng Hansen He, and Changmeng Cai Significance: An anti-semaphorin-4D vascular Significance: ZBTB7A is recruited to the E2F-Rb binding targeting agent demonstrates antitumor and prosurvival sites by AR and negatively regulates the transcriptional effects but also unravels a novel promalignant effect involving activity of E2F1 on DNA replication genes. macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients. See related commentary, p. 5146

5342 Heparanase Accelerates Obesity-Associated 5394 Nanoparticle Encapsulation of Synergistic Breast Cancer Progression Immune Agonists Enables Systemic Codelivery Esther Hermano, Rachel Goldberg, Ariel M. Rubinstein, to Tumor Sites and IFNb-Driven Antitumor Amir Sonnenblick, Bella Maly, Daniela Nahmias, Immunity Jin-Ping Li, Marinka A.H. Bakker, Johan van der Vlag, Prabhani U. Atukorale, Shruti P. Raghunathan, Israel Vlodavsky, Tamar Peretz, and Michael Elkin Vanitha Raguveer, Taylor J. Moon, Carolyn Zheng, Significance: This study reveals the role of heparanase Peter A. Bielecki, Michelle L. Wiese, Amy L. Goldberg, in promoting obesity-associated breast cancer and Gil Covarrubias, Christopher J. Hoimes, and provides a mechanistically informed approach to Efstathios Karathanasis uncouple obesity and breast cancer in a rapidly Significance: Systemic administration of an immuno- growing population of obese patients. nanoparticle in a murine breast tumor model drives a robust tumor site–specific APC response by delivering two 5355 Stearoyl-CoA Desaturase 1 Protects Ovarian synergistic immune-potentiating molecules, highlighting Cancer Cells from Ferroptotic Cell Death the potential of nanoparticles for immunotherapy. Lia Tesfay, Bibbin T. Paul, Anna Konstorum, Zhiyong Deng, Anderson O. Cox, Jingyun Lee, Cristina M. Furdui, Poornima Hegde, Frank M. Torti, CONVERGENCE AND TECHNOLOGIES and Suzy V. Torti Significance: The combination of SCD1 inhibitors and 5407 An Activatable Cancer-Targeted Hydrogen

H NR NR + ferroptosis inducers may provide a new therapeutic H2O2 Peroxide Probe for Photoacoustic and −

H2O2 - reactive group

An activatable and cancer-targeted hydrogen peroxide probe enables photoacoustic molecular strategy for the treatment of ovarian cancer patients. imaging in a mouse model of breast cancer. Fluorescence Imaging © 2019 American Association for Cancer Research See related commentary, p. 5149 Judith Weber, Laura Bollepalli, Ana M. Belenguer, Marco Di Antonio, Nicola De Mitri, James Joseph, Shankar Balasubramanian, Christopher A. Hunter, and Sarah E. Bohndiek TRANSLATIONAL SCIENCE Significance: This study presents the first activatable and cancer-targeted hydrogen peroxide probe for photoacoustic 5367 Meflin-Positive Cancer-Associated Fibroblasts molecular imaging, paving the way for visualization of

Early-stage cancer Advanced-stage cancer Meﬂin Inhibit Pancreatic Carcinogenesis hydrogen peroxide at high spatiotemporal resolution in Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida,

Meﬂin+/αSMAlow PSCs or CAFs Meﬂinlow/-/αSMA+ CAFs (Cancer-restraining CAFs)

Meﬂin+PSCs or CAFs suppress PDAC progression by inhibiting ECM remodeling; they however give rise to Meﬂinlow/-/α SMA+CAFs, which promote PDAC progression. living subjects. © 2019 American Association for Cancer Research Naoya Asai, Atsushi Masamune, Akitoshi Hara, Nobutoshi Esaki, Kaori Ushida, Shinji Mii, – Yukihiro Shiraki, Kenju Ando, Liang Weng, 5418 Quantification and Localization of Protein RNA Seiichiro Ishihara, Suzanne M. Ponik, Interactions in Patient-Derived Archival Tumor Matthew W. Conklin, Hisashi Haga, Arata Nagasaka, Tissue Takaki Miyata, Makoto Matsuyama, Tomoe Kobayashi, Emmeline L. Blanchard, Danae Argyropoulou, Tsutomu Fujii, Suguru Yamada, Junpei Yamaguchi, Chiara Zurla, Sushma M. Bhosle, Daryll Vanover, and Tongtong Wang, Susan L. Woods, Daniel Worthley, Philip J. Santangelo Teppei Shimamura, Mitsuhiro Fujishiro, Significance: This work presents an approach to sensitively, Yoshiki Hirooka, Atsushi Enomoto, and specifically, and quantitatively detect and localize native Masahide Takahashi mRNA and protein interactions for analysis of abnormal Significance: Meflin marks and functionally contributes to post-transcriptional regulation in patient-derived archival a subset of cancer-associated fibroblasts that exert tumor samples. antitumoral effects.

5382 In Vivo Modeling of Chemoresistant POPULATION AND PREVENTION SCIENCE Neuroblastoma Provides New Insights into Chemorefractory Disease and Metastasis 5432 MALAT1 rs664589 Polymorphism Inhibits Orli Yogev, Gilberto S. Almeida, Karen T. Barker, Binding to miR-194-5p, Contributing to Sally L. George, Colin Kwok, James Campbell, Colorectal Cancer Risk, Growth, and Metastasis Magdalena Zarowiecki, Dimitrios Kleftogiannis, Shenshen Wu, Hao Sun, Yajie Wang, Xi Yang, Laura M. Smith, Albert Hallsworth, Philip Berry, Qingtao Meng, Hongbao Yang, Haitao Zhu, Weiyan Tang, Till Mocklinghoff,€ Hannah T. Webber, Xiaobo Li, Michael Aschner, and Rui Chen Laura S. Danielson, Bliss Buttery, Elizabeth A. Calton, Significance: These findings highlight the functional Barbara M. da Costa, Evon Poon, Yann Jamin, role of MALAT1 polymorphism in colorectal cancer Stefano Lise, Gareth J. Veal, Neil Sebire, metastasis and survival as well as the underlying Simon P. Robinson, John Anderson, and Louis Chesler mechanism. Significance: An in vivo mouse model of high-risk treatment-resistant neuroblastoma exhibits changes in the tumor microenvironment, widespread metastases, and sensitivity to JAK1/2 inhibition. vii

5442 High Levels of C-Reactive Protein Are Associated CORRECTION with an Increased Risk of Ovarian Cancer: Results from the Ovarian Cancer Cohort 5457 Correction: An Inhibitor of the Pleckstrin Consortium Homology Domain of CNK1 Selectively Lauren C. Peres, Adrianne R. Mallen, Mary K. Townsend, BlockstheGrowthofMutantKRASCellsand Elizabeth M. Poole, Britton Trabert, Naomi E. Allen, Tumors Alan A. Arslan, Laure Dossus, Renee T. Fortner, Martin Indarte, Roisin Puentes, Marco Maruggi, Inger T. Gram, Patricia Hartge, Annika Idahl, Nathan T. Ihle, Geoffrey Grandjean, Michael Scott, Rudolf Kaaks, Marina Kvaskoff, Anthony M. Magliocco, Zamal Ahmed, Emmanuelle J. Meuillet, Shuxing Zhang, Melissa A. Merritt, J. Ramón Quirós, Anne Tjonneland, Robert Lemos Jr, Lei Du-Cuny, Fabiana I.A.L. Layng, Antonia Trichopoulou, Rosario Tumino, Ricardo G. Correa, Laurie A. Bankston, Carla H. van Gils, Kala Visvanathan, Robert C. Liddington, Lynn Kirkpatrick, and Nicolas Wentzensen, Anne Zeleniuch-Jacquotte, and Garth Powis Shelley S. Tworoger Significance: C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be EDITOR'S NOTE particularly implicated in the etiology of mucinous and endometrioid carcinomas. 5458 Editor's Note: Estrogen Receptor a Promotes Breast Cancer by Reprogramming Choline Metabolism Min Jia, Trygve Andreassen, Lasse Jensen, RESOURCE REPORT Tone Frost Bathen, Indranil Sinha, Hui Gao, Chunyan Zhao, Lars-Arne Haldosen, Yihai Cao, 5452 Curatopes Melanoma: A Database of Predicted Leonard Girnita, Siver Andreas Moestue, and T-cell Epitopes from Overly Expressed Proteins in Karin Dahlman-Wright Metastatic Cutaneous Melanoma Christopher Lischer, Martin Eberhardt, Tanushree Jaitly, Cornelia Schinzel, Niels Schaft, Jan Dorrie,€ RETRACTION Gerold Schuler, and Julio Vera Significance: A database is presented that predicts and 5459 Retraction: The Raf Inhibitor BAY 43-9006 scores antitumor T-cell epitopes, with a focus on tolerability (Sorafenib) Induces Caspase-Independent and avoidance of severe autoimmunity, offering a Apoptosis in Melanoma Cells supplementary epitope set for further investigation in David J. Panka, Wei Wang, Michael B. Atkins, and immunotherapy. James W. Mier

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viii

ABOUT THE COVER

Chemotherapeutic elimination (green) of the tumor is a complex challenge. Mathematical modeling of tumor-immune interactions reveals that optimal therapy, which may initially seem black and white, requires delicate navigation through a complex multidimensional landscape personalized to each patient. Cytotoxic efficacy (purple) must be balanced with supporting patient antitumor immune responses stimulated by lymphodepletion (blue). Optimal therapy treads an intermediate path (gold) that maintains dosing within a maximally effective window. The authors acknowledge the help of Dr. Chandler D. Gatenbee who provided coding expertise on the coloring for the image. For details, see article by Park and colleagues on page 5302.

Cancer Res 2019;79:5129-5459.

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