BREAKING INSIGHTS

4443 Highlights from Recent Cancer Literature

PRIORITY REPORTS

4445 Kras and Tp53 Mutations Cause Cholangiocyte-and Hepatocyte-Derived CholangiocarcinomaMargaret A. Hill, William B. Alexander, Bing Guo,Yasutaka Kato, Krushna Patra, Michael R. O'Dell,Matthew N. McCall, Christa L. Whitney-Miller,Nabeel Bardeesy, and Aram F. Hezel

Significance: The histopathogenesis of biliary tract cancer,driven by Tp53 and Kras mutations, can be differentiallyimpacted by the cell of origin within the mature liver as wellby major epidemiological risk factors.

4452 Recurrent RARB Translocations in AcutePromyelocytic Leukemia Lacking RARATranslocationTomoo Osumi, Shin-ichi Tsujimoto, Moe Tamura,Meri Uchiyama, Kazuhiko Nakabayashi, Kohji Okamura,Masanori Yoshida, Daisuke Tomizawa, Akihiro Watanabe,Hiroyuki Takahashi, Tsukasa Hori, Shohei Yamamoto,Kazuko Hamamoto, Masahiro Migita,Hiroko Ogata-Kawata, Toru Uchiyama, Hiroe Kizawa,Hitomi Ueno-Yokohata, Ryota Shirai, Masafumi Seki,Kentaro Ohki, Junko Takita, Takeshi Inukai, Seishi Ogawa,Toshio Kitamura, Kimikazu Matsumoto, Kenichiro Hata,Nobutaka Kiyokawa, Susumu Goyama, andMotohiro Kato

Significance: These findings report a novel and distinctgenetic subtype of acute promyelocytic leukemia (APL) byillustrating that the majority of APL without RARAtranslocations harbor RARB translocations.

METABOLISM AND CHEMICAL BIOLOGY

4459 Aberrant FGFR Tyrosine Kinase SignalingEnhances the Warburg Effect by ReprogrammingLDH Isoform Expression and Activity inProstate CancerJunchen Liu, Guo Chen, Zezhen Liu, Shaoyou Liu,Zhiduan Cai, Pan You, Yuepeng Ke, Li Lai, Yun Huang,Hongchang Gao, Liangcai Zhao, Helene Pelicano,Peng Huang, Wallace L. McKeehan, Chin-Lee Wu,Cong Wang, Weide Zhong, and Fen Wang

Significance: FGF signaling drives the Warburg effectthrough differential regulation of LDHA and LDHB, therebypromoting the progression of prostate cancer.

4471 PDSS2 Deficiency Induces Hepatocarcinogenesisby Decreasing Mitochondrial Respiration andReprogramming Glucose MetabolismYan Li, Shuhai Lin, Lei Li, Zhi Tang, Yumin Hu,Xiaojiao Ban, Tingting Zeng, Ying Zhou, Yinghui Zhu,Song Gao, Wen Deng, Xiaoshi Zhang, Dan Xie,Yunfei Yuan, Peng Huang, Jinjun Li, Zongwei Cai, andXin-Yuan Guan

Significance: Downregulation of PDSS2 is a driving factorin hepatocellular carcinoma tumorigenesis.

4482 Enhanced Glycolysis Supports Cell Survival inEGFR-Mutant Lung Adenocarcinoma byInhibiting Autophagy-Mediated EGFRDegradationJi Hye Kim, Boas Nam, Yun Jung Choi, Seon Ye Kim,Jung-Eun Lee, Ki Jung Sung, Woo Sung Kim,Chang-Min Choi, Eun-Ju Chang, Jae Soo Koh,Joon Seon Song, Shinkyo Yoon, Jae Cheol Lee,Jin Kyung Rho, and Jaekyoung Son

Significance: Enhanced glycolysis by EGFR mutation isrequired for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale foruse of JNK activators in patients with EGFR-mutatedNSCLC.

MOLECULAR CELL BIOLOGY

4497 R-spondin3 Is Associated with Basal-ProgenitorBehavior in Normal and Tumor Mammary CellsJohanna M. Tocci, Carla M. Felcher, Martín E. García Sol�a,María Victoria Goddio, María Noel Zimberlin,Natalia Rubinstein, Anabella Srebrow, Omar A. Coso,Martín C. Abba, Roberto P. Meiss, and Edith C. Kordon

Significance: These findings identify RSPO3 as a potentialtherapetuic target in basal-like breast cancers.

4512 DDX3 Activates CBC-eIF3–Mediated Translationof uORF-Containing Oncogenic mRNAs toPromote Metastasis in HNSCCHung-Hsi Chen, Hsin-I. Yu, Muh-Hwa Yang, andWoan-Yuh Tarn

Significance: The discovery of DDX3-mediated expression ofoncogenic uORF-containing genes expands knowledge ontranslational control mechanisms and provides potentialtargets for cancer therapy.

August 15, 2018 � Volume 78 � Number 16

Cancer Research

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4524 Expression of Long Noncoding RNA YIYAPromotes Glycolysis in Breast CancerZhen Xing, Yanyan Zhang, Ke Liang, Liang Yan, Yu Xiang,Chunlai Li, Qingsong Hu, Feng Jin, Vasanta Putluri,Nagireddy Putluri, Cristian Coarfa, Arun Sreekumar,Peter K. Park, Tina K. Nguyen, Shouyu Wang,Jianwei Zhou, Yan Zhou, Jeffrey R. Marks,David H. Hawke, Mien-Chie Hung, Liuqing Yang,Leng Han, Haoqiang Ying, and Chunru Lin

Significance: These findings offer a first glimpse into how along-coding RNA influences cancer metabolism to drivetumor growth.

4533 The Endosomal Protein CEMIP Links WNTSignaling to MEK1–ERK1/2 Activation inSelumetinib-Resistant Intestinal OrganoidsHong Quan Duong, Ivan Nemazanyy, Florian Rambow,Seng Chuan Tang, Sylvain Delaunay, Lars Tharun,Alexandra Florin, Reinhard B€uttner, Daniel Vandaele,Pierre Close, Jean-Christophe Marine, Kateryna Shostak,and Alain Chariot

Significance: MEK1 inhibitor-resistant colorectal cancerrelies on the scaffold and endosomal protein CEMIP tomaintain ERK1/2 signaling and Myc-driven transcription.

4549 Transcription Factor YY1 Promotes CellProliferation by Directly Activating the PentosePhosphate PathwayShourong Wu, Huimin Wang, Yanjun Li, Yudan Xie,Can Huang, Hezhao Zhao, Makoto Miyagishi, andVivi Kasim

Significance: This study reveals a novel role for YY1 inregulating G6PD and activating the pentose phosphatepathway, linking its function in tumorigenesis to metabolicreprogramming.

4563 Long Noncoding RNA CRYBG3 BlocksCytokinesis by Directly Binding G-ActinHailong Pei, Wentao Hu, Ziyang Guo, Huaiyuan Chen,Ji Ma, Weidong Mao, Bingyan Li, Aiqing Wang,Jianmei Wan, Jian Zhang, Jing Nie, Guangming Zhou,and Tom K. Hei

Significance: Identification of the long noncoding RNALNC CRYBG3 as a mediator of microfilamentdisorganization marks it as a novel therapeutic antitumorstrategy.

TUMOR BIOLOGY AND IMMUNOLOGY

4573 CD4þ T-cell–Mediated Rejection of MHCClass II–Positive Tumor Cells Is Dependent onAntigen Secretion and Indirect Presentationon Host APCsOle Audun W. Haabeth, Marte Fauskanger,Melanie Manzke, Katrin U. Lundin, Alexandre Corthay,Bjarne Bogen, and Anders A. Tveita

Significance: Elimination of tumors by CD4þ T cellsrecognizing secreted tumor neoantigens can occur in theabsence of tumor cell-intrinsic MHC II expression,highlighting the potential clinical relevance of indirectantigen recognition by tumor-infiltrating APC.

4586 Hypoxic Tumor-Derived Exosomal miR-301aMediates M2 Macrophage Polarization viaPTEN/PI3Kg to Promote Pancreatic CancerMetastasisXiaofengWang, Guangtao Luo, Kundong Zhang, Jun Cao,Chen Huang, Tao Jiang, Bingya Liu, Liping Su, andZhengjun Qiu

Significance: These findings identify an exosomal miRNAcritical for microenvironmental cross-talk that may prove tobe a potential target for diagnosis and treatment ofpancreatic cancer.

4599 Inactivation of Citron Kinase InhibitsMedulloblastoma Progression by InducingApoptosis and Cell SenescenceGianmarco Pallavicini, Francesco Sgrò, Francesca Garello,Mattia Falcone, Valeria Bitonto, Gaia E. Berto,Federico T. Bianchi, Marta Gai, Alessandra M.A. Chiotto,Miriam Filippi, Juan C. Cutrin, Ugo Ala, Enzo Terreno,Emilia Turco, and Ferdinando Di Cunto

Significance: In vitro and in vivo proof of conceptidentifies citron kinase protein as a suitable target formedulloblastoma treatment.

4613 Attenuated TRAF3 Fosters Activation ofAlternative NF-kB and Reduced Expression ofAntiviral Interferon, TP53, and RB to PromoteHPV-Positive Head and Neck CancersJialing Zhang, Tony Chen, Xinping Yang, Hui Cheng,Stephan S. Sp€ath, Paul E. Clavijo, Jianhong Chen,Christopher Silvin, Natalia Issaeva, Xiulan Su,Wendell G. Yarbrough, Christina M. Annunziata,Zhong Chen, and Carter Van Waes

Significance: These findings report the functional role ofTRAF3 as a tumor suppressor that modulates the malignantphenotype of HPVþ head and neck cancers.

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4627 Mapping the HLA Ligandome of ColorectalCancer Reveals an Imprint of Malignant CellTransformationMarkus W. L€offler, Daniel J. Kowalewski, Linus Backert,J€org Bernhardt, Patrick Adam, Heiko Schuster,Florian Dengler, Daniel Backes, Hans-Georg Kopp,Stefan Beckert, Silvia Wagner, Ingmar K€onigsrainer,Oliver Kohlbacher, Lothar Kanz, Alfred K€onigsrainer,Hans-Georg Rammensee, Stefan Stevanovi�c, andSebastian P. Haen

Significance: Cancer-associated pathways are reflected inthe antigenic landscape of colorectal cancer, suggesting thattumor-specific antigens do not necessarily have to bemutation-derived but may also originate from otheralterations in cancer cells.

4642 Tipifarnib Inhibits HRAS-DrivenDedifferentiated Thyroid CancersBrian R. Untch, Vanessa Dos Anjos,Maria E.R. Garcia-Rendueles, Jeffrey A. Knauf,Gnana P. Krishnamoorthy, Mahesh Saqcena,Umeshkumar K. Bhanot, Nicholas D. Socci, Alan L. Ho,Ronald Ghossein, and James A. Fagin

Significance: Tipifarnib effectively inhibits oncogenicHRAS-driven tumorigenesis and abrogating adaptivesignaling improves responses. NF1 and GNAS mutationsdrive acquired resistance to Hras inhibition, supporting theon-target effects of the drug.

4658 The Canonical Wnt Pathway DrivesMacropinocytosis in CancerGil Redelman-Sidi, Anna Binyamin, Isabella Gaeta,Wilhelm Palm, Craig B. Thompson, Paul B. Romesser,Scott W. Lowe, Mukta Bagul, John G. Doench,David E. Root, and Michael S. Glickman

Significance: The Wnt pathway drives macropinocytosis incancer cells, thereby contributing to cancer growth innutrient-deficient conditions and, in the context of coloncancer, to the early phases of oncogenesis.

4671 Epithelial–Mesenchymal Transition in HumanProstate Cancer Demonstrates EnhancedImmune Evasion Marked by IDO1 ExpressionKimberley Kolijn, Esther I. Verhoef, Marcel Smid,Ren�e B€ottcher, Guido W. Jenster, Reno Debets, andGeert J.L.H. van Leenders

Significance: These findings demonstrate EMT is linked toan immunosuppressive environment in clinical prostatecancer, suggesting that patients with prostate cancer canpotentially benefit from combinatorial drug therapy.

4680 SHP-1 Acts as a Tumor Suppressor inHepatocarcinogenesis and HCC ProgressionLiang-ZhiWen, Kai Ding, Ze-RuiWang, Chen-Hong Ding,Shu-Juan Lei, Jin-Pei Liu, Chuan Yin, Ping-Fang Hu,Jin Ding, Wan-Sheng Chen, Xin Zhang, and Wei-Fen Xie

Significance: The nonreceptor protein tyrosine phosphataseSHP-1 acts as a tumor suppressor in hepatocellularcarcinoma.

4692 CRISPR/Cas9-Mediated Knockout of DGKImproves Antitumor Activities of HumanT CellsIn-Young Jung, Yoon-Young Kim, Ho-Sung Yu,Myoungsoo Lee, Seokjoong Kim, and Jungmin Lee

Significance: This novel study demonstrates efficientablation of diacylglycerol kinase in human CAR-T cellsthat leads to improved antitumor immunity and may havesignificant impact in human cancer immunotherapy.

4704 Mcl-1 Phosphorylation without DegradationMediates Sensitivity to HDAC Inhibitors byLiberating BH3-Only ProteinsJingshan Tong, Xingnan Zheng, Xiao Tan,Rochelle Fletcher, Zaneta Nikolovska-Coleska, Jian Yu,and Lin Zhang

Significance: These findings present a novel degradation-independent function of Mcl-1 phosphorylation inanticancer therapy that could be useful for developing newMcl-1–targeting agents to overcome therapeutic resistance.

4716 Neoadjuvant-Intensive Androgen DeprivationTherapy Selects for Prostate Tumor Foci withDiverse Subclonal Oncogenic AlterationsAdam G. Sowalsky, Huihui Ye, Manoj Bhasin,Eliezer M. Van Allen, Massimo Loda, Rosina T. Lis,Laleh Montaser-Kouhsari, Carla Calagua, Fen Ma,JoshuaW. Russo, Rachel J. Schaefer, Olga S. Voznesensky,Zhenwei Zhang, Glenn J. Bubley, Bruce Montgomery,Elahe A. Mostaghel, Peter S. Nelson, Mary-Ellen Taplin,and Steven P. Balk

Significance: Neoadjuvant androgen deprivation therapyfor prostate cancer selects for tumor foci with subclonalgenomic alterations, which may comprise the origin ofmetastatic castration-resistant prostate cancer.

TRANSLATIONAL SCIENCE

4731 Circulating Tumor Cells Undergoing EMTProvide a Metric for Diagnosis and Prognosis ofPatients with Hepatocellular CarcinomaLu-Nan Qi, Bang-De Xiang, Fei-Xiang Wu, Jia-Zhou Ye,Jian-Hong Zhong, Yan-Yan Wang, Yuan-Yuan Chen,Zu-Shun Chen, Liang Ma, Jie Chen, Wen-Feng Gong,Ze-Guang Han, Yan Lu, Jin-Jie Shang, and Le-Qun Li

Significance: In liver cancer, CTC examination mayrepresent an important ''liquid biopsy'' tool to detect bothearly disease and recurrent or metastatic disease, providingcues for early intervention or adjuvant therapy.

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4745 CD271þ Cells Are Diagnostic and Prognosticand Exhibit Elevated MAPK Activity in SHHMedulloblastomaLisa Liang, Ludivine Coudi�ere-Morrison, Nazanin Tatari,Margaret Stromecki, Agnes Fresnoza,Christopher J. Porter, Marc R. Del Bigio,Cynthia Hawkins, Jennifer A. Chan, Timothy C. Ryken,Michael D. Taylor, Vijay Ramaswamy, andTamra E. Werbowetski-Ogilvie

Significance: This study identifies CD271 as a specific andnovel biomarker of SHH-type medulloblastoma and thattargeting CD271þ cells through MEK inhibition representsa novel therapeutic strategy for the treatment of SHHmedulloblastoma.

4760 EWS/ETS-Driven Ewing Sarcoma Requires BETBromodomain ProteinsParadesi Naidu Gollavilli, Aishwarya Pawar,Kari Wilder-Romans, Ramakrishnan Natesan,Carl G. Engelke, Vijaya L. Dommeti,Pranathi M. Krishnamurthy, Archana Nallasivam,Ingrid J. Apel, Tianlei Xu, Zhaohui S. Qin, Felix Y. Feng,and Irfan A. Asangani

Significance: These findings reveal the dependency ofEWS/ETS transcription factors on BET epigenetic readerproteins and demonstrate the potential of BET inhibitors forthe treatment of Ewing sarcoma.

CONVERGENCE AND TECHNOLOGIES

4774 Combined MR Imaging of Oxygen Consumptionand Supply Reveals Tumor Hypoxia andAggressiveness in Prostate Cancer PatientsTord Hompland, Knut Ha

�konHole, Harald Bull Ragnum,

Eva-Katrine Aarnes, Ljiljana Vlatkovic, A. Kathrine Lie,Sebastian Patzke, Bjørn Brennhovd, Therese Seierstad,and Heidi Lyng

Significance: These findings present a novel imagingstrategy that indirectly measures tumor hypoxia and haspotential application in a wide variety of solid tumors andother imaging modalities.

4786 LIFEx: A Freeware for Radiomic FeatureCalculation in Multimodality Imaging toAccelerate Advances in the Characterizationof Tumor HeterogeneityChristophe Nioche, Fanny Orlhac, Sarah Boughdad,Sylvain Reuz�e, Jessica Goya-Outi, Charlotte Robert,Claire Pellot-Barakat, Michael Soussan,Fr�ed�erique Frouin, and Ir�ene Buvat

Significance: This study presents a user-friendly, multi-platform freeware to extract radiomic features from PET,SPECT, MR, CT, and US images, or any combination ofimaging modalities.

POPULATION AND PREVENTION SCIENCE

4790 Influence of Smoking, Body Mass Index,and Other Factors on the Preventive Effectof Nonsteroidal Anti-Inflammatory Drugs onColorectal Cancer RiskXiaoliang Wang, Andrew T. Chan, Martha L. Slattery,Jenny Chang-Claude, John D. Potter, Steven Gallinger,Bette Caan, Johanna W. Lampe, Polly A. Newcomb,Niha Zubair, Li Hsu, Robert E. Schoen,Michael Hoffmeister, Hermann Brenner,Loic Le Marchand, Ulrike Peters, and Emily White

Significance: Obesity and heavy smoking attenuate thebenefit of aspirin use for colorectal cancer prevention.

CORRECTION

4800 Correction: Significance of MAD2 Expression toMitotic Checkpoint Control in Ovarian CancerCells

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ABOUT THE COVER

Tumor microheterogeneity is common and subclones in primary tumors are potentialmediators of tumor progression. Laser capture microdissection was used to isolate foci ofresidual tumor (purple and green) that remained after regression of the bulk tumor (red) inradical prostatectomy specimens from patients with prostate cancer treated for 6 months withneoadjuvant intensive androgen deprivation therapy. Whole exome sequencing identified foci-specific oncogenic alterations, including losses of RB1, BRCA2, or PTEN, indicating that thetumor prior to therapy contained subclones that were castration-resistant by distinctmechanisms. These subclones may evolve further and may be the origin of metastaticcastration-resistant prostate cancer, and their early detection may allow for more effectiveadjuvant therapy. For details, see article by Sowalsky and colleagues on page 4716.

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2018;78:4443-4800. Cancer Res     78 (16)

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