BREAKING INSIGHTS

1125 Highlights from Recent Cancer Literature

GENOME AND EPIGENOME

1127 A KDM5 Inhibitor Increases Global H3K4Trimethylation Occupancy and Enhances theBiological Efficacy of 5-Aza-20-DeoxycytidineBenjamin R. Leadem, Ioannis Kagiampakis,Catherine Wilson, Tommy K. Cheung, David Arnott,Patrick Trojer, Marie Classon, Hariharan Easwaran, andStephen B. Baylin

Significance: This study offers a first look into the moleculareffects of a novel KDM5 inhibitory compound, suggestinghow its use in combination with DNA methylation inhibitorspresents new opportunities to explore in translational cancerepigenetics.

1140 Race Disparities in the Contribution of miRNAIsoforms and tRNA-Derived Fragments toTriple-Negative Breast CancerAristeidis G. Telonis and Isidore Rigoutsos

Significance: This big data-driven study comparing normaland cancer transcriptomes uncovers RNA expressiondifferences between Caucasian and African-Americanpatients with triple-negative breast cancer that might helpexplain disparities in incidence and aggressive character.

MOLECULAR CELL BIOLOGY

1155 Loss of RASSF4 Expression in Multiple MyelomaPromotes RAS-Driven Malignant ProgressionEva De Smedt, Ken Maes, Stefaan Verhulst, Hui Lui,Alboukadel Kassambara, Anke Maes, Nicolas Robert,Carlo Heirman, Andrew Cakana, Dirk Hose,Karine Breckpot, Leo A. van Grunsven, Kim De Veirman,Eline Menu, Karin Vanderkerken, J�erôme Moreaux, andElke De Bruyne

Significance: These findings provide a mechanistic rationalefor combining trametinib with HDAC inhibitors orbortezomib in patients with multiple myeloma whose tumorsexhibit low RASSF4 expression.

1169 Long Noncoding RNA pancEts-1 PromotesNeuroblastoma Progression throughhnRNPK-Mediated b-Catenin StabilizationDan Li, Xiaojing Wang, Hong Mei, Erhu Fang, Lin Ye,Huajie Song, Feng Yang, Huanhuan Li, Kai Huang,Liduan Zheng, and Qiangsong Tong

Significance: These findings reveal the oncogenic functionsof a long noncoding RNA in neuroblastoma progression,offering a potential target for clinical therapeutics.

1184 FIH Is an Oxygen Sensor in Ovarian Cancer forG9a/GLP-Driven Epigenetic Regulation ofMetastasis-Related GenesJengmin Kang, Seung-Hyun Shin, Haejin Yoon, June Huh,Hyun-Woo Shin, Yang-Sook Chun, and Jong-Wan Park

Significance: These findings deepen understanding ofoxygen-dependent gene regulation and cancer metastasis inresponse to hypoxia.

1200 Familial and Somatic BAP1 Mutations InactivateASXL1/2-Mediated Allosteric Regulation of BAP1Deubiquitinase by Targeting MultipleIndependent DomainsHongzhuang Peng, Jeremy Prokop, Jayashree Karar,Kyewon Park, Li Cao, J. William Harbour,Anne M. Bowcock, S. Bruce Malkowicz, Mitchell Cheung,Joseph R. Testa, and Frank J. Rauscher III

Significance: Combined computational and biochemicalapproaches demonstrate that the BAP1-ASXL2 interaction isdirect and high affinity and that many BAP1 mutations actallosterically to inhibit BAP1–ASXL2 binding.

1214 O-GlcNAcylation of the Tumor SuppressorFOXO3 Triggers Aberrant Cancer Cell GrowthHeon Shin, Hyun-Jeong Cha, Keun Na, Min Jung Lee,Jin-Young Cho, Chae-Yeon Kim, Eun Kyung Kim,Chang Moo Kang, Hoguen Kim, and Young-Ki Paik

Significance: These findings highlight a posttranslationalmechanism for indirect abrogation of the p53 pathway, onethat may occur with some frequency in human cancer cells.

TUMOR BIOLOGY AND IMMUNOLOGY

1225 The CARMA3–Bcl10–MALT1 SignalosomeDrives NFkB Activation and PromotesAggressiveness in Angiotensin IIReceptor–Positive Breast CancerPrasanna Ekambaram, Jia-Ying (Lloyd) Lee,Nathaniel E. Hubel, Dong Hu, Saigopalakrishna Yerneni,Phil G. Campbell, Netanya Pollock, Linda R. Klei,Vincent J. Concel, Phillip C. Delekta, Arul M. Chinnaiyan,Scott A. Tomlins, Daniel R. Rhodes, Nolan Priedigkeit,Adrian V. Lee, Steffi Oesterreich, LindaM.McAllister-Lucas,and Peter C. Lucas

Significance: These findings offer a mechanistic rationale toexplore the repurposing of drugs that target angiotensinaction to improve the treatment of AGTR1-expressing breastcancers.

March 1, 2018 � Volume 78 � Number 5

Cancer Research

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1241 Nkx2.8 Inhibits Epithelial–MesenchymalTransition in Bladder Urothelial Carcinoma viaTranscriptional Repression of Twist1Chunping Yu, Zhuowei Liu, Qiuhong Chen,Yonghong Li, Lijuan Jiang, Zhiling Zhang, andFangjian Zhou

Significance: These findings highlight a novel EMTsignaling axis as a candidate target for therapeuticintervention in advanced urothelial carcinomas.

1253 Therapy-Educated Mesenchymal Stem CellsEnrich for Tumor-Initiating CellsMichael Timaner, Nitzan Letko-Khait, Ruslana Kotsofruk,Madeleine Benguigui, Ofrat Beyar-Katz,Chen Rachman-Tzemah, Ziv Raviv, Tomer Bronshtein,Marcelle Machluf, and Yuval Shaked

Significance: These results establish a mechanism by whichmesenchyme stem cells in the tumor microenvironmentpromote chemoresistance, and they propose a novel drugdelivery system to overcome this challenge.

1266 Deletion of the von Hippel-Lindau Genein Hemangioblasts Causes Hemangioblastoma-like Lesions in Murine RetinaHerui Wang, Matthew J. Shepard, Chao Zhang,Lijin Dong, Dyvon Walker, Liliana Guedez, Stanley Park,Yujuan Wang, Shida Chen, Ying Pang, Qi Zhang,Chun Gao, Wai T. Wong, Henry Wiley, Karel Pacak,Emily Y. Chew, Zhengping Zhuang, and Chi-Chao Chan

Significance: This study describes a model thatphenotypically recapitulates a form of retinal pathogenesisthat is driven by genetic loss of the VHL tumor suppressor,providing a useful tool for its study and therapeuticintervention.

1275 GADD45b Loss Ablates InnateImmunosuppression in CancerDaniela Verzella, Jason Bennett, Mariafausta Fischietti,Anil K. Thotakura, Camilla Recordati, Fabio Pasqualini,Daria Capece, Davide Vecchiotti, Daniel D’Andrea,Barbara Di Francesco, Marcella De Maglie,Federica Begalli, Laura Tornatore, Salvatore Papa,Toby Lawrence, Stuart J. Forbes, Antonio Sica,Edoardo Alesse, Francesca Zazzeroni, andGuido Franzoso

Significance: These findings define a myeloid-basedimmune checkpoint that restricts T-cell trafficking intotumors, with potentially important therapeutic implicationsto generally improve the efficacy of cancer immunotherapy.

1293 Inflammasome Adaptor ASC SuppressesApoptosis of Gastric Cancer Cells by anIL18-Mediated Inflammation-IndependentMechanismVirginie Deswaerte, Paul Nguyen, Alison West,Alison F. Browning, Liang Yu, Saleela M. Ruwanpura,Jesse Balic, Thaleia Livis, Charlotte Girard,Adele Preaudet, Hiroko Oshima, Ka Yee Fung, Hazel Tye,Meri Najdovska, Matthias Ernst, Masanobu Oshima,Cem Gabay, Tracy Putoczki, and Brendan J. Jenkins

Significance: Inflammasome activation that elevates IL18helps drive gastric cancer by protecting cancer cells againstapoptosis, with potential implications for new therapeuticstrategies in this setting.

1308 Germinal Centers Determine the PrognosticRelevance of Tertiary Lymphoid Structures andAre Impaired by Corticosteroids in LungSquamous Cell CarcinomaKarīna Silina, Alex Soltermann,Farkhondeh Movahedian Attar, Ruben Casanova,Zina M. Uckeley, Helen Thut, Muriel Wandres,Sergejs Isajevs, Phil Cheng,Alessandra Curioni-Fontecedro, Periklis Foukas,Mitchell P. Levesque, Holger Moch, Aija Lin�e, andMaries van den Broek

Significance: Corticosteroid treatment duringchemotherapy negatively affects the development of tertiarylymphoid structures and abrogates their prognostic valuein patients with lung cancer.

1321 Inactivation of Cancer-Associated-FibroblastsDisrupts Oncogenic Signaling in PancreaticCancer Cells and Promotes Its RegressionPatricia Dauer, Xianda Zhao, Vineet K. Gupta,Nikita Sharma, Kousik Kesh, Prisca Gnamlin,Vikas Dudeja, Selwyn M. Vickers, Sulagna Banerjee, andAshok Saluja

Significance: In an established mouse model of pancreaticcancer, administration of the promising experimentaldrug Minnelide was found to actively deplete reactivestromal fibroblasts and to trigger tumor regression, withimplications for stromal-based strategies to attack thisdisease.

1334 Combined Mutation of Apc, Kras, andTgfbr2 Effectively Drives Metastasis ofIntestinal CancerEri Sakai, Mizuho Nakayama, Hiroko Oshima,Yuta Kouyama, Atsushi Niida, Satoshi Fujii,Atsushi Ochiai, Keiichi I. Nakayama, Koshi Mimori,Yutaka Suzuki, Chang Pyo Hong, Chan-Young Ock,Seong-Jin Kim, and Masanobu Oshima

Significance: These findings illuminate how key drivermutations in colon cancer cooperate to drive thedevelopment of metastatic disease, with potentialimplications for the development of suitable preventionstrategies.

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TRANSLATIONAL SCIENCE

1347 Statin-Induced Cancer Cell Death Can BeMechanistically Uncoupled from Prenylation ofRAS Family ProteinsRosemary Yu, Joseph Longo, Jenna E. van Leeuwen,Peter J. Mullen, Wail Ba-Alawi, Benjamin Haibe-Kains,and Linda Z. Penn

Significance: The use of statins to target cancer cell EMTmay be useful as a therapy to block cancer progression.

1358 Brain-Mimetic 3D Culture Platforms AllowInvestigation of Cooperative Effects ofExtracellular Matrix Features on TherapeuticResistance in GlioblastomaWeikun Xiao, Rongyu Zhang, Alireza Sohrabi,Arshia Ehsanipour, Songping Sun, Jesse Liang,Christopher M. Walthers, Lisa Ta, David A. Nathanson,and Stephanie K. Seidlits

Significance: Three-dimensional culture scaffolds ofglioblastoma provide a better physiological representationover current methods of patient-derived cell culture andxenograft models.

CORRECTION

1371 Correction: KLF6 Suppresses Metastasis of ClearCell Renal Cell Carcinoma via TranscriptionalRepression of E2F1

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ABOUT THE COVER

Tertiary lymphoid structures (TLS) develop in the human tumor microenvironment andcorrelate with prolonged survival. TLS are organized structures that resemble follicles of lymphnodes and contribute to local immune responses. Using immunofluorescence and quantitativepathology on human lung cancer andmouse lung samples, it was shown that TLS developmentfollowed sequential steps from simple lymphocytic aggregates to organized structures withlymphoid stromal cells and finally to mature TLS with a germinal center. Neoadjuvantchemotherapy and corticosteroid treatment significantly reduced the development of matureTLS, which was associated with poor outcome in patients with lung cancer. For details, seearticle by Silina and colleagues on page 1308.

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2018;78:1125-1372. Cancer Res     78 (5)

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