BREAKING ADVANCES

3963 Highlights from Recent Cancer Literature

REVIEW

3965 Long Noncoding RNA and Cancer: A NewParadigmArunoday Bhan, Milad Soleimani, andSubhrangsu S. Mandal

PRIORITY REPORT

3982 Epithelial-to-Mesenchymal Transition Contributesto Immunosuppression in Breast CarcinomasAnushka Dongre, Mohammad Rashidian, Ferenc Reinhardt,Aaron Bagnato, Zuzana Keckesova, Hidde L. Ploegh, andRobert A. Weinberg

Pr�ecis: Immune cells and immunomodulatory markers protectlocal tumor cells from immune attack and can be potentiallytargeted to enhance the sensitivity of tumors to therapy.

MOLECULAR AND CELLULARPATHOBIOLOGY

3990 SIRT3-Mediated Dimerization of IDH2 DirectsCancer Cell Metabolism and Tumor GrowthXianghui Zou, Yueming Zhu, Seong-Hoon Park,Guoxiang Liu, Joseph O'Brien, Haiyan Jiang, andDavid Gius

Pr�ecis: These findings identify SIRT3 as a potential tumorsuppressor, mediating its effects by limiting the ability of IDH2to drive cancer cell metabolism and malignant progression.

4000 Arl13b Promotes Gastric Tumorigenesis byRegulating Smo Trafficking and Activation of theHedgehog Signaling PathwayJia Shao, Linlin Xu, Limin Chen, Quqin Lu, Xinsheng Xie,Wei Shi, Huanting Xiong, Chao Shi, Xuan Huang,Jinhong Mei, Hai Rao, Hua Lu, Nonghua Lu, andShiwen Luo

Pr�ecis: Arl13b plays crucial roles in Smo-mediated signaltransduction, activation of the Hh pathway, and tumorgrowth of gastric cancer, which may be a potential novelmolecule target for the development of anticancer therapy.

4014 IGFBP7 Deletion Promotes HepatocellularCarcinomaMaaged Akiel, Chunqing Guo, Xia Li, Devaraja Rajasekaran,Rachel G. Mendoza, Chadia L. Robertson, Nidhi Jariwala,Fang Yuan, Mark A. Subler, Jolene Windle, Dawn K. Garcia,Zhao Lai, Hung-I Harry Chen, Yidong Chen,Shah Giashuddin, Paul B. Fisher, Xiang-Yang Wang, andDevanand Sarkar

Pr�ecis: IGFBP7 acts as a tumor suppressor gene thatsuppresses liver cancer, both by directly inhibiting cancer cellgrowth and by stimulating an antitumor immune response,with therapeutic implications to improve liver cancermanagement.

4026 Autocrine BMP-4 Signaling Is a Therapeutic Targetin Colorectal CancerYuichiro Yokoyama, Toshiaki Watanabe, Yusuke Tamura,Yoshinobu Hashizume, Kohei Miyazono, andShogo Ehata

Pr�ecis: A growth factor that is part of the TGFb family isimplicated in this study as a new target for the treatment ofcolorectal cancer.

TUMOR AND STEM CELL BIOLOGY

4039 A Naturally Generated Decoy of the ProstateApoptosis Response-4 Protein Overcomes TherapyResistance in TumorsNikhil Hebbar, Ravshan Burikhanov, Nidhi Shukla,Shirley Qiu, Yanming Zhao, Kojo S.J. Elenitoba-Johnson,and Vivek M. Rangnekar

Pr�ecis: PAF, a novel fragment of the tumor suppressorPar-4, may be harnessed to induce paracrine growthinhibition of heterogeneous tumors and overcometherapeutic resistance.

4051 ARHGAP18 Downregulation by miR-200bSuppresses Metastasis of Triple-NegativeBreast Cancer by Enhancing Activation of RhoABrock Humphries, Zhishan Wang, Yunfei Li, Jing-Ru Jhan,Yiguo Jiang, and Chengfeng Yang

Pr�ecis: Studies of a RhoGAP overexpressed in aggressivetriple-negative breast cancers contradict the conventionalview that RhoGAP family members function as tumorsuppressors.

August 1, 2017 � Volume 77 � Number 15

Cancer Research

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4065 Intestine-Specific Homeobox Gene ISX IntegratesIL6 Signaling, Tryptophan Catabolism, andImmune SuppressionLi-Ting Wang, Shyh-Shin Chiou, Chee-Yin Chai,Edward Hsi, Kazunari K. Yokoyama, Shen-Nien Wang,Shau-Ku Huang, and Shih-Hsien Hsu

Pr�ecis: This seminal study identifies the IL6-inducible proto-oncogene ISX in organizing a forward feedback loop oftumoral immune suppression in liver cancer that employs theIDO1-kynurenine-AHR pathway and the immuneregulatory molecule PD-L1, with implications for improvingtherapeutic management.

4078 Comprehensive Evaluation of Protein CodingMononucleotide Microsatellites in Microsatellite-Unstable Colorectal CancerJohanna Kondelin, Alexandra E. Gylfe, Sofie Lundgren,Tomas Tanskanen, Jiri Hamberg, Mervi Aavikko,Kimmo Palin, Heikki Ristolainen, Riku Katainen,Eevi Kaasinen, Minna Taipale, Jussi Taipale,Laura Renkonen-Sinisalo, Heikki J€arvinen, Jan B€ohm,Jukka-Pekka Mecklin, Pia Vahteristo, Sari Tuupanen,Lauri A. Aaltonen, and Esa Pitk€anen

Pr�ecis: These findings present a new statistical model forevaluation of mutation significance in microsatellites andidentify novel candidate driver genes, which provide newinsight into the tumorigenesis of microsatellite unstablecolorectal cancer.

4089 Identification of New Tumor Suppressor Genes inTriple-Negative Breast CancerRoberto Rangel, Liliana Guzman-Rojas,Takahiro Kodama, Michiko Kodama, Justin Y. Newberg,Neal G. Copeland, and Nancy A. Jenkins

Pr�ecis: This study demonstrates the utility of two-stepforward genetic screens using the engineered SleepingBeauty transposon system in mice, offering an invaluabletool to identify novel candidate therapeutic pathways andtargets.

THERAPEUTICS, TARGETS, AND CHEMICALBIOLOGY

4102 The Alkylating Chemotherapeutic TemozolomideInduces Metabolic Stress in IDH1-Mutant Cancersand Potentiates NADþ Depletion–MediatedCytotoxicityKensuke Tateishi, Fumi Higuchi, Julie J. Miller,Mara V.A. Koerner, Nina Lelic, Ganesh M. Shankar,Shota Tanaka, David E. Fisher, Tracy T. Batchelor,A. John Iafrate, Hiroaki Wakimoto, Andrew S. Chi, andDaniel P. Cahill

Pr�ecis: Mutations in the metabolic enzyme IDH1 exposespecific metabolite vulnerabilities during DNA repairresponse to chemotherapy-induced damage, which can beexploited for therapeutic effect.

4116 b-Catenin Is a Candidate Therapeutic Target forMyeloid Neoplasms with del(5q)Liping Li, Yue Sheng, Wenshu Li, Chao Hu, Nupur Mittal,Kaoru Tohyama, Amber Seba, You-Yang Zhao,Howard Ozer, Tongyu Zhu, and Zhijian Qian

Pr�ecis: These results suggest a strategy to eliminate leukemicstem cells, which drive a common chromosomally definedclass of myeloid neoplasms, perhaps enabling anindividualized treatment for this subset of leukemia patients.

4127 Monitoring the Vascular Response and Resistanceto Sunitinib in Renal Cell Carcinoma In Vivo withSusceptibility Contrast MRISimon P. Robinson, Jessica K.R. Boult, Naveen S. Vasudev,and Andrew R. Reynolds

Pr�ecis: This study illustrates how a noninvasive magneticresonance imaging method can track vascular phenotypes,which correspond with therapeutic responses produced by anantiangiogenic drug in kidney tumors.

MICROENVIRONMENT AND IMMUNOLOGY

4135 Enhanced Therapeutic Efficacy and Memory ofTumor-Specific CD8 T Cells by Ex Vivo PI3K-dInhibitionRasha Abu Eid, Shamim Ahmad, Yuan Lin, Mason Webb,Zuzana Berrong, Rajeev Shrimali, Takumi Kumai,Sudha Ananth, Paulo C. Rodriguez, Esteban Celis,John Janik, Mikayel Mkrtichyan, and Samir N. Khleif

Pr�ecis: These findings highlight clinical implications forPI3K-d inhibition in CD8 T cells, which appear to enhancethe efficacy of adoptive cell transfer therapies and vaccine-based immunotherapies.

4146 Immune Checkpoint Blockade, ImmunogenicChemotherapy or IFN-a Blockade Boost the Localand Abscopal Effects of Oncolytic VirotherapyLaetitia Fend, Takahiro Yamazaki, Christelle Remy,Catherine Fahrner, Murielle Gantzer, Virginie Nourtier,Xavier Pr�eville, Eric Qu�em�eneur, Oliver Kepp, Julien Adam,Aur�elien Marabelle, Jonathan M. Pitt, Guido Kroemer, andLaurence Zitvogel

Pr�ecis: These findings suggest how to optimize the effects ofoncolytic vaccinia viruses used to treat cancer, using methodsto improve the efficacy of immune cells infiltrating local anddistant tumors.

4158 An Immunosuppressive Dendritic Cell SubsetAccumulates at Secondary Sites and PromotesMetastasis in Pancreatic CancerJustin A. Kenkel, WilliamW. Tseng, Matthew G. Davidson,Lorna L. Tolentino, Okmi Choi, Nupur Bhattacharya,E. Scott Seeley, Daniel A. Winer, Nathan E. Reticker-Flynn,and Edgar G. Engleman

Pr�ecis: An immunosuppressive DC population can betargeted in multiple ways to stimulate tumor immunity andprevent disease progression in PDAC.

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INTEGRATED SYSTEMS ANDTECHNOLOGIES

4171 3D Mathematical Modeling of GlioblastomaSuggests That Transdifferentiated VascularEndothelial Cells Mediate Resistance to CurrentStandard-of-Care TherapyHuaming Yan, Mónica Romero-López, Lesly I. Benitez,Kaijun Di, Hermann B. Frieboes,Christopher C.W. Hughes, Daniela A. Bota, andJohn S. Lowengrub

Pr�ecis: These striking findings suggest that usingcombinatorial therapies to target transdifferentiated vascularendothelial cells present in glioblastomas could eradicatethese deadly brain tumors without recurrence.

4185 Competition between DNA Methylation,Nucleotide Synthesis, and Antioxidation inCancer versus Normal TissuesSha Cao, Xiwen Zhu, Chi Zhang, Hong Qian,Heinz-Bernd Schuttler, Jianping Gong, and Ying Xu

Pr�ecis: Reduced global DNA methylation levels in cancercells versus normal cells are regulated by competition for keymetabolites, whose shifting levels may serve as potentialprognostic markers for cancer.

PREVENTION AND EPIDEMIOLOGY

4196 Risk of Second Malignancies in Solid OrganTransplant Recipients Who DevelopKeratinocyte CancersRachel D. Zamoiski, Elizabeth Yanik, Todd M. Gibson,Elizabeth K. Cahoon, Margaret M. Madeleine,Charles F. Lynch, Sally Gustafson, Marc T. Goodman,Melissa Skeans, Ajay K. Israni, Eric A. Engels, andLindsay M. Morton

Pr�ecis: Second cancer risks after keratinocyte cancers in solidorgan transplant recipients differ somewhat from the generalpopulation, providing insight into the immunosuppressiveroots of squamous cell carcinogenesis.

CORRECTION

4204 Correction: Noninvasive In Vivo Imaging andBiologic Characterization of Thyroid Tumors byImmunoPET Targeting of Galectin-3

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ABOUT THE COVER

Mesenchymal carcinoma cells recruit immunosuppressive Tregs and M2 macrophages to thetumormicroenvironment relative to their epithelial counterparts, which recruit cytotoxic CD8þ

T cells instead. In carcinomas that are comprised of heterogeneous mixtures of both epithelialand mesenchymal cells, minority subpopulations of immunosuppressive mesenchymalcarcinoma cells are able to protect the entire tumor, including its epithelial cells, from immuneattack. Immunofluorescence analysis of mixed tumor sections revealed that mesenchymal(green) and epithelial (white) carcinoma cells segregate to distinct sectors of the tumor. F480þ

macrophages (red) are interspersed only among the mesenchymal cells of the tumor, whileonly a few scattered macrophages are found at the periphery of epithelial sectors within thesame tumor. For details, see article by Dongre and colleagues on page 3982.

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2017;77:3963-4204. Cancer Res     77 (15)

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