BREAKING ADVANCES

5349 Highlights from Recent Cancer Literature

REVIEW

5351 Crosstalk between microRNA30a/b/c/d/e-5pand the Canonical Wnt Pathway: Implicationsfor Multiple Myeloma therapyJian-Jun Zhao and Ruben D. Carrasco

MEETING REPORT

5359 Biomimetic Tissue–Engineered Systems forAdvancing Cancer Research: NCI StrategicWorkshop ReportTeresa K. Schuessler, Xin Yi Chan,Huanhuan Joyce Chen, Kyungmin Ji,Kyung Min Park, Alireza Roshan-Ghias,Pallavi Sethi, Archana Thakur, Xi Tian,Aranzazu Villasante, Ioannis K. Zervantonakis,Nicole M. Moore, Larry A. Nagahara, andNastaran Z. Kuhn

PRIORITY REPORTS

5364 Aurora-A Inhibition Offers a Novel TherapyEffective against Intracranial GlioblastomaJames R. Van Brocklyn, Jeffrey Wojton,Walter H. Meisen, David A. Kellough,Jeffery A. Ecsedy, Balveen Kaur, andNorman L. Lehman

Pr�ecis: These results offer preclinical proof-of-concept for amitotic kinase inhibitor as a new therapeutic for the mostdeadly type of brain cancer.

5371 Molecular Changes in Lobular Breast Cancersin Response to Endocrine TherapyLaura M. Arthur, Arran K. Turnbull,Victoria L. Webber, Alexey A. Larionov,Lorna Renshaw, Charlene Kay, Jeremy S. Thomas,J. Michael Dixon, and Andrew H. Sims

Pr�ecis: Molecular responses to aromatase inhibition aresimilar in lobular and ductal breast tumors, despite clearhistologic differences before and after treatment, withimplications for the use of aromatase inhibitors in breastcancer treatment.

5377 Oral Interleukin-10 Alleviates Polyposis viaNeutralization of Pathogenic T-RegulatoryCellsAllen Y. Chung, Qingsheng Li, Sarah J. Blair,Magdia De Jesus, Kristen L. Dennis, Charles LeVea,Jin Yao, Yijun Sun, Thomas F. Conway,Lauren P. Virtuoso, Nicholas G. Battaglia,Stacia Furtado, EdithMathiowitz, Nicholas J. Mantis,Khashayarsha Khazaie, and Nejat K. Egilmez

Pr�ecis: Striking findings suggest that IL10 might beadministered orally as a microparticle formulation that canbe used to reprogram the inflammatory state of intestinalimmunity in colon cancer–prone patients to reduce theirrisk of cancer development.

INTEGRATED SYSTEMS AND TECHNOLOGIES

5386 Dynamics of Leukemia Stem-like CellExtinction in Acute Promyelocytic LeukemiaBenjamin Werner, Robert E. Gallagher,Elisabeth M. Paietta, Mark R. Litzow,Martin S. Tallman, Peter H. Wiernik, James L. Slack,Cheryl L. Willman, Zhuoxin Sun, Arne Traulsen, andDavid Dingli

Pr�ecis: By combining a mathematical model ofhematopoiesis with data from a large randomized trial ofacute promyelocytic leukemia, this study offers the firstdetermination of the average duration of therapy requiredto eliminate all stem-like cells in a human tumor.

5397 Sentinel Lymph Node Biopsy Revisited:Ultrasound-Guided Photoacoustic Detection ofMicrometastases Using Molecularly TargetedPlasmonic NanosensorsGeoffrey P. Luke, Jeffrey N. Myers,Stanislav Y. Emelianov, and Konstantin V. Sokolov

Pr�ecis: This important study describes a rapid,noninvasive method to detect micrometastases in sentinellymph nodes, providing an alternative to traditionalsentinel node analyses that are widely used to stageresectable tumors.

October 1, 2014 � Volume 74 � Number 19

Cancer Research

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MICROENVIRONMENT AND IMMUNOLOGY

5409 Cryotherapy with Concurrent CpGOligonucleotide Treatment Controls LocalTumor Recurrence and Modulates HER2/neuImmunityJesse J. Veenstra, HeatherM.Gibson, Peter J. Littrup,Joyce D. Reyes, Michael L. Cher, Akira Takashima,and Wei-Zen Wei

Pr�ecis: The liberation of tumor-associated antigens byfreezing tumors in situ cooperates with peritumoral CpGinjection to increase innate and adaptive immunity,leveraging aminimally invasive treatment for patients whoare not candidates for surgical resection.

5421 Paclitaxel Therapy Promotes Breast CancerMetastasis in a TLR4-Dependent MannerLisa Volk-Draper, Kelly Hall, Caitlin Griggs,Sandeep Rajput, Pascaline Kohio, David DeNardo,and Sophia Ran

Pr�ecis: These provocative findings suggest that expressionof the Toll-like receptor TLR4 on cancer cells changes theirsystemic reaction to treatment with paclitaxel, a drug usedwidely in the oncology clinic, promoting risks of future drugresistance and metastatic disease.

5435 Novel Paracrine Modulation of Notch–DLL4Signaling by Fibulin-3 Promotes Angiogenesisin High-Grade GliomasMohan S. Nandhu, Bin Hu, Susan E. Cole,Anat Erdreich-Epstein, Diego J. Rodriguez-Gil, andMariano S. Viapiano

Pr�ecis: This study focuses on a proangiogenic signal thatmediates anti-VEGF resistance in aggressive brain tumors,with implications on how to improve antiangiogenictherapy in this setting, where anti-VEGF treatments arewidely used clinically but with little frank efficacy.

5449 Gangliosides Drive the Tumor Infiltration andFunction of Myeloid-Derived Suppressor CellsAssefa Wondimu, Yihui Liu, Yan Su, Daniel Bobb,Jennifer S.Y. Ma, Lina Chakrabarti, Sasa Radoja, andStephan Ladisch

Pr�ecis: This important article suggests thatimmunosuppressive gangliosides, a type of glycolipid shedby many human tumors, function to attract MDSC into thetumor environment, suggesting a broadly applicablestrategy to thwart this common mechanism of immuneescape.

5458 Acquired Resistance to FractionatedRadiotherapy Can Be Overcome byConcurrent PD-L1 BlockadeSimon J. Dovedi, Amy L. Adlard,Grazyna Lipowska-Bhalla, Conor McKenna,Sherrie Jones, Eleanor J. Cheadle, Ian J. Stratford,Edmund Poon, Michelle Morrow, Ross Stewart,Hazel Jones, Robert W. Wilkinson,Jamie Honeychurch, and Tim M. Illidge

Pr�ecis: The benefits of fractionated radiotherapy incancer patients might be improved greatly by blocking anadaptive mechanism of immunosuppression that limitstherapeutic efficacy, with immediate implications forclinical evaluation of a new type of combinationimmunoradiotherapy.

MOLECULAR AND CELLULARPATHOBIOLOGY

5469 Complex Formation and Function of EstrogenReceptor a in Transcription Requires RIP140Meritxell Rosell, Ekaterina Nevedomskaya,Suzan Stelloo, Jaya Nautiyal, Ariel Poliandri,Jennifer H. Steel, Lodewyk F.A. Wessels,Jason S. Carroll, Malcolm G. Parker, andWilbert Zwart

Pr�ecis: A transcriptional coregulator involved in energyhomeostasis, ovulation, and mammary gland developmentis found to play a critical role in breast cancer and theresponse to tamoxifen treatment.

5480 CDC42 Inhibition Suppresses Progression ofIncipient Intestinal TumorsRyotaro Sakamori, Shiyan Yu, Xiao Zhang,Andrew Hoffman, Jiaxin Sun, Soumyashree Das,Pavan Vedula, Guangxun Li, Jiang Fu,Francesca Walker, Chung S. Yang, Zheng Yi,Wei Hsu, Da-Hai Yu, Lanlan Shen,Alexis J. Rodriguez, Makoto M. Taketo,Edward M. Bonder, Michael P. Verzi, and Nan Gao

Pr�ecis: A Rho family small GTPase activated in early-stage APC/b-catenin–driven colorectal cancers may offera biomarker and therapeutic target to prevent progression.

5493 EFA6B Antagonizes Breast CancerJos�ephine Zangari, Mariagrazia Partisani,Francois Bertucci, Julie Milanini, Ghislain Bidaut,Carole Berruyer-Pouyet, Pascal Finetti, Elodie Long,Fr�ed�eric Brau, Olivier Cabaud, Bruno Chetaille,Daniel Birnbaum, Marc Lopez, Paul Hofman,Michel Franco, and Fr�ed�eric Luton

Pr�ecis: A regulator of tight junction and apico-basalpolarity in breast cancer cells prevents EMT, and its loss iscorrelated with the aggressive behavior of triple-negativeand basal-like breast cancers, with implications for newtherapeutic targets in these largely intractable diseases.

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5507 The SIRT1/HIF2a Axis Drives ReductiveGlutamine Metabolism under ChronicAcidosis and Alters Tumor Response toTherapyCyril Corbet, Nihed Draoui, Florence Polet,Adan Pinto, Xavier Drozak, Olivier Riant, andOlivier Feron

Pr�ecis: While extracellular tumor acidosis is largelydescribed as the main consequence of the high glycolyticflux in cancer cells, the current study demonstrates that, inturn, tumor cells may shift their metabolism towardglutamine to adapt to acidosis.

5520 PAK1 Tyrosine Phosphorylation Is Required toInduce Epithelial–Mesenchymal Transitionand Radioresistance in Lung Cancer CellsEunGi Kim, HyeSook Youn, TaeWoo Kwon,Beomseok Son, JiHoon Kang, Hee Jung Yang,Ki Moon Seong, Wanyeon Kim, and BuHyun Youn

Pr�ecis: These results offer a preclinical rationale for theuse of JAK2 inhibitors to radiosensitize lungadenocarcinomas based on blockade of a PAK1 kinase-dependent pathway that mediates EMT andradioresistance in this setting.

5532 Transcriptional Dynamics in ColorectalCarcinogenesis: New Insights into the Role ofc-Myc and miR17 in Benign to CancerTransformationEyal Ben-David, Assaf C. Bester, Sagiv Shifman, andBatsheva Kerem

Pr�ecis: This study sheds light on the temporal process ofhow neoplastic transformation occurs in normal colontissue cells, with new information on the roles of c-Myc andmiR-17 in the development of colorectal cancer.

5541 Uncontrolled Inflammation Induced by AEG-1Promotes Gastric Cancer and Poor PrognosisGuanghua Li, Zhao Wang, Jinning Ye,Xinhua Zhang, Hui Wu, Jianjun Peng, Wu Song,Chuangqi Chen, Shirong Cai, Yulong He, andJianbo Xu

Pr�ecis: An oncogenic protein also known as themetastasis-associated protein MTDH is found to functionin a vicious positive feedback loop of TLR4–NF-kBinflammatory signaling, with implications for therapeuticstrategies to limit cancer progression.

PREVENTION AND EPIDEMIOLOGY

5553 GBV-C Infection and Risk of NHL among U.S.AdultsCindy M. Chang, Jack T. Stapleton,Donna Klinzman, James H. McLinden,Mark P. Purdue, Hormuzd A. Katki, andEric A. Engels

Pr�ecis: This provocative study suggests the likelihood of acausative role for a viral infection in subsequentdevelopment of non-Hodgkin lymphoma.

THERAPEUTICS, TARGETS, AND CHEMICALBIOLOGY

5561 Antitumor Efficacy of a Bispecific AntibodyThat Targets HER2 and Activates T CellsTeemu T. Junttila, Ji Li, Jennifer Johnston,Maria Hristopoulos, Robyn Clark, Diego Ellerman,Bu-Er Wang, Yijin Li, Mary Mathieu, Guangmin Li,Judy Young, Elizabeth Luis, Gail Lewis Phillips,Eric Stefanich, Christoph Spiess, Andrew Polson,Bryan Irving, Justin M. Scheer, Melissa R. Junttila,Mark S. Dennis, Robert Kelley, Klara Totpal, andAllen Ebens

Pr�ecis: These results highlight a new type of potentimmunotherapy for HER2þ breast cancer, which targetsHER2, delivers T cells to HER2þ tumors, and can be furtherleveraged with PD-L1 antibody to help defeat tumoralimmune escape, engendering more durable therapeuticresponses.

5572 EGFR Blockade Enriches for Lung CancerStem–like Cells through Notch3-DependentSignalingRajeswara Rao Arasada, Joseph M. Amann,Mohammad A. Rahman, Stacey S. Huppert, andDavid P. Carbone

Pr�ecis: These findings may explain why some studies ofthe EGFR inhibitor erlotinib appeared to worsen survivalin early-stage lung cancer patients, implicating a novelcombination regimen to overcome this effect.

5585 Translesion Polymerase h Is Upregulated byCancer Therapeutics and Confers AnticancerDrug ResistanceMaja T. Tomicic, Dorthe Aasland,Steffen C. Naumann, Ruth Meise,Christina Barckhausen, Bernd Kaina, andMarkus Christmann

Pr�ecis: Induction of a particular DNA repair polymeraseby DNA-crosslinking drugs limits their cancer cell killingactivity, with implications for how to best use these types ofdrugs.

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TUMOR AND STEM CELL BIOLOGY

5597 SIX1 Promotes Tumor Lymphangiogenesis byCoordinating TGFb Signals That IncreaseExpression of VEGF-CDan Liu, Li Li, Xiao-Xue Zhang, Dong-Yi Wan,Bi-Xin Xi, Zheng Hu, Wen-Cheng Ding, Da Zhu,Xiao-Li Wang, Wei Wang, Zuo-Hua Feng,Hui Wang, Ding Ma, and Qing-Lei Gao

Pr�ecis: These findings suggest mechanistic insights intothe formation of tumoral lymph vessels that can drainmetastatic cells to distant sites, with possible implicationsfor blocking this process as a therapeutic strategy.

5608 A Comprehensive DNA Methylation Profile ofEpithelial-to-Mesenchymal TransitionF. Javier Carmona, VeronicaDavalos, EnriqueVidal,Antonio Gomez, Holger Heyn, Yutaka Hashimoto,Miguel Vizoso, Anna Martinez-Cardus,Sergi Sayols, Humberto J. Ferreira,Jose V. S�anchez-Mut, Sebasti�an Mor�an,Mireia Margelı, Eva Castella, Maria Berdasco,Olafur A. Stefansson, Jorunn E. Eyfjord,Eva Gonzalez-Suarez, Joaquın Dopazo,Modesto Orozco, Ivo G. Gut, and Manel Esteller

Pr�ecis: An understanding of how global DNA methylationpatterns are altered by EMT in cancer may more deeplyilluminate common pathogenic processes and broad-based prognostic markers.

5620 Trim32 Facilitates Degradation of MYCN onSpindle Poles and Induces Asymmetric CellDivision in Human Neuroblastoma CellsHideki Izumi and Yasuhiko Kaneko

Pr�ecis: These results offer important insights intoasymmetric cell division, a special type of cell division instem cells also found to occur in cancer stem-like cells,adding to the ongoing discussion of what precisely defines"stemness'' in cancer cells.

5631 Androgen Receptor Is the Key TranscriptionalMediator of the Tumor Suppressor SPOP inProstate CancerChuandong Geng, Kimal Rajapakshe,Shrijal S. Shah, John Shou, Vijay Kumar Eedunuri,Christopher Foley, Warren Fiskus,Mahitha Rajendran, Sue Anne Chew,Martin Zimmermann, Richard Bond, Bin He,Cristian Coarfa, and Nicholas Mitsiades

Pr�ecis: These results offer a mechanistic explanationfor understanding the basis of the tumor suppressoractivity of an E3 ubiquitin ligase adapter that is mutatedin �15% of human prostate cancers.

5644 NQO1 Suppresses NF-kB–p300 Interaction toRegulate Inflammatory Mediators Associatedwith Prostate TumorigenesisDinesh Thapa, Peng Meng, Roble G. Bedolla,Robert L. Reddick, Addanki P. Kumar, andRita Ghosh

Pr�ecis: Genetic findings suggest that a pivotal regulator ofredox status can promote androgen independence inprostate cancer cells by helping establish a self-reinforcinginflammatory microenvironment.

5656 PRMT7 Induces Epithelial-to-MesenchymalTransition and Promotes Metastasis in BreastCancerRuosi Yao, Hao Jiang, Yuhui Ma, Liping Wang,Lin Wang, Juan Du, Pingfu Hou, Yanyan Gao,Li Zhao, Guannan Wang, Yu Zhang, Dong-Xu Liu,Baiqu Huang, and Jun Lu

Pr�ecis: These results define a protein argininemethyltransferase as an inducer of breast cancermetastasis, with potential implications for thedevelopment of a targeted therapeutic to treat highlyinvasive breast cancers.

5668 IGF1R Inhibition in Mammary EpitheliaPromotes Canonical Wnt Signaling and Wnt1-Driven TumorsLauren M. Rota, Lidia Albanito, Marcus E. Shin,Corey L. Goyeneche, Sain Shushanov,Emily J. Gallagher, Derek LeRoith,Deborah A. Lazzarino, and Teresa L. Wood

Pr�ecis: Although IGF1R inhibitors are being considered fortreatment of basal-like breast cancers, the results of thispreclinical study suggest that attenuating IGF1R in thecontext of activated Wnt signaling leads to negativeoutcomes in this disease subtype, with possibleimplications for attendant clinical cautions.

CORRECTION

5680 Correction: Role of the Neural Niche in BrainMetastatic Cancer

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ABOUT THE COVER

Oral administration of BSA-FITC-loaded polylactic acid microparticles (green) prepared via phaseinversion nanoencapsulation (PIN) resulted in rapid uptake (within 15 minutes) and persistence(for at least 24 hours) in the Peyer's patches (PP) of 10 week-old APCmin/þ mice (magenta,dendritic cells; blue, B-cells). Uptake in the PP was followed by trafficking of the particles to themesenteric lymph nodes. Particles could not be visualized in the villi or the enterocytes of the smallintestine or in the colon. Oral IL-10 PIN particles ameliorated intestinal polyposis and systemicsymptoms of disease in the APCmin/þ mice via neutralization of CD4þFoxp3þRORgtþIL-17þpathogenic T-regulatory cells found in the immune structures of the gastrointestinal tract. Fordetails, see article by Chung and colleagues on page 5377.

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