BREAKING INSIGHTS

3527 Highlights from Recent Cancer Literature

REVIEW

3529 Exosomal Induction of Tumor InnervationPaola D. Vermeer

CANCER RESEARCH HIGHLIGHTS

3536 New Functions of Long Noncoding RNAsduring EMT and Tumor ProgressionChunlai Li

See related article, p. 3542

3539 The Gut Microbiome: A New Player in BreastCancer MetastasisWendy V. Ingman

See related article, p. 3662

GENOME AND EPIGENOME

3542 SATB2-AS1 Suppresses Colorectal CarcinomaAggressiveness by Inhibiting SATB2-DependentSnail Transcription and Epithelial–MesenchymalTransitionYi-Qing Wang, Dong-Mei Jiang, Sha-Sha Hu, Li Zhao,Lan Wang, Min-Hui Yang, Mei-Ling Ai, Hui-Juan Jiang,Yue Han, Yan-Qing Ding, and Shuang Wang

Significance: These data show that the lncRNASATB2-AS1 mediates epigenetic regulation of SATB2and Snail expression to suppress colorectal cancerprogression.

See related commentary, p. 3536

METABOLISM AND CHEMICAL BIOLOGY

3557 Magnetic Resonance Imaging Is More SensitiveThan PET for Detecting Treatment-Induced CellDeath–Dependent Changes in GlycolysisRichard L. Hesketh, Jiazheng Wang, Alan J. Wright,David Y. Lewis, Alice E. Denton, Richard Grenfell,Jodi L. Miller, Robert Bielik, Marcel Gehrung, Maria Fala,Susana Ros, Bangwen Xie, De-en Hu, and KevinM. Brindle

Significance: These findings demonstrate superior sensitivityof MRI measurement of hyperpolarized [1-13C]pyruvatemetabolism versus PET measurement of 18F-FDG uptake fordetecting early changes in glycolysis following treatment-induced tumor cell death.

MOLECULAR CELL BIOLOGY

CCND1

ClHOO

O

ClNH

YK-4-279

DHX9

pncCCND1_BEWS-FLI1

Sam68, DHX9, and pncCCND1_B form a multimolecular inhibitory complex on the CCND1promoter, fostered by EWS-FLI1 dissociation and counteracted by mitogenic stimuli,such as IGF1 stimulation.

Sam68

3570 The Promoter-Associated Noncoding RNApncCCND1_B Assembles a Protein–RNA Complexto Regulate Cyclin D1 Transcription in EwingSarcomaRamona Palombo, Paola Frisone, Marco Fidaleo,Neri Mercatelli, Claudio Sette, and Maria Paola Paronetto

Significance: A pncRNA-based mechanism repressesexpression of CCND1 through the formation of a protein–RNA complex and provides new therapeutic opportunitiesfor patients with Ewing sarcoma.

3583 A Model System for Studying the DNMT3AHotspot Mutation (DNMT3AR882) Demonstrates aCausal Relationship between Its Dominant-Negative Effect and LeukemogenesisRui Lu, JunWang, Zhihong Ren, Jiekai Yin, YinshengWang,Ling Cai, and Gang Greg Wang

Significance: These findings highlight a model system tostudy the functional impact of a hotspot mutation ofDNMT3A at R882 in leukemia.

3595 Bortezomib Stabilizes and Activates p53 inProliferative Compartments of Both Normaland Tumor Tissues In VivoYuezhen Xue, Nick Barker, Shawn Hoon, Pingping He,Teena Thakur, Shifana Raja Abdeen,Priadarsini Maruthappan, Farid J. Ghadessy, andDavid P. Lane

Significance: These findings show that bortezomib is lessactive in p53-defective tumors, yet its success in treatingmultiple myeloma suggests its use can be extended top53-proficient solid tumors.

July 15, 2019 � Volume 79 � Number 14

Cancer Research

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3608 Chemotherapy-Induced Extracellular VesiclemiRNAs Promote Breast Cancer Stemness byTargeting ONECUT2Meng Shen, Chuan Dong, Xianhui Ruan, Wei Yan,Minghui Cao, Donald Pizzo, Xiwei Wu, Lin Yang,Liang Liu, Xiubao Ren, and Shizhen Emily Wang

Significance: These findings reveal a critical mechanism ofresistance to chemotherapy by which breast cancer cellssecrete miRNA-containing extracellular vesicles tostimulate cancer stem cell-like features.

TUMOR BIOLOGY AND IMMUNOLOGY

3622 MicroRNA-92 Expression in CD133þ MelanomaStem Cells Regulates Immunosuppression in theTumor Microenvironment via Integrin-Dependent Activation of TGFbChris Shidal, Narendra P. Singh, Prakash Nagarkatti, andMitzi Nagarkatti

Significance: CD133þ cells play an active role insuppressing melanoma antitumor immunity by modulatingmiR-92, which increases influx of immunosuppressivecells and TGFb1 expression.

3636 Asporin Restricts Mesenchymal Stromal CellDifferentiation, Alters the TumorMicroenvironment, and Drives MetastaticProgressionRobert M. Hughes, Brian W. Simons, Hamda Khan,Rebecca Miller, Valentina Kugler, Samantha Torquato,Debebe Theodros, Michael C. Haffner, Tamara Lotan,Jessie Huang, Elai Davicioni, Steven S. An, Ryan C. Riddle,Daniel L.J. Thorek, Isla P. Garraway, Elana J. Fertig,John T. Isaacs, W. Nathaniel Brennen, Ben H. Park, andPaula J. Hurley

Significance: These findings show that asporin regulateskey properties of mesenchymal stromal cells, including self-renewal and multipotency, and asporin expression byreactive stromal cells alters the tumor microenvironmentand promotes metastatic progression.

3651 Cancer-Associated Fibroblasts Produce Netrin-1to Control Cancer Cell PlasticityPei-Ju Sung, Nicolas Rama, Jeromine Imbach,Stephany Fiore, Benjamin Ducarouge, David Neves,Huei-Wen Chen, David Bernard, Pan-Chyr Yang,Agn�es Bernet, Stephane Depil, and Patrick Mehlen

Significance:Netrin-1, a navigation cue during embryonicdevelopment, is upregulated in cancer-associated fibroblastsand regulates cancer cell stemness.

3662 Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Inflammation andTumor Cell Dissemination in HormoneReceptor–Positive Breast CancerClaire Buchta Rosean, Raegan R. Bostic,Joshua C.M. Ferey, Tzu-Yu Feng, Francesca N. Azar,Kenneth S. Tung, Mikhail G. Dozmorov,Ekaterina Smirnova, Paula D. Bos, andMelanie R. Rutkowski

Significance: Identification of commensal dysbiosis as ahost-intrinsic factor mediating evolution of metastaticbreast cancer allows for development of interventions ordiagnostic tools for patients at highest risk for developingmetastatic disease.

See related commentary, p. 3539

3676 HDAC3 Deficiency Promotes Liver Cancerthrough a Defect in H3K9ac/H3K9me3TransitionHongjie Ji, Yongjie Zhou, Xiang Zhuang, Yongjie Zhu,Zhenru Wu, Yannrong Lu, Shengfu Li, Yong Zeng,Qing R. Lu, Yanying Huo, Yujun Shi, and Hong Bu

Significance: These findings show that HDAC3 exclusivelyregulates H3K9ac in response to DNA damage, and loss ofHDAC3 activity shifts the balance from DNA damagecontrol to protumorigenic transcriptional activity.

3689 Transketolase Deficiency Protects the Liverfrom DNA Damage by Increasing Levels ofRibose 5-Phosphate and NucleotidesMinle Li, Ying Lu, Yakui Li, Lingfeng Tong,Xiao-chuan Gu, Jian Meng, Yemin Zhu, Lifang Wu,Ming Feng, Na Tian, Ping Zhang, Tianle Xu, Shu-Hai Lin,and Xuemei Tong

Significance: These findings identify transketolase as anovel metabolic target to maintain genome stability andreduce liver carcinogenesis.

3702 IL12 Abrogates Calcineurin-Dependent ImmuneEvasion during Leukemia ProgressionJennifer L. Rabe, Lori Gardner, Rae Hunter,Jairo A. Fonseca, Jodi Dougan, Christy M. Gearheart,Michael S. Leibowitz, Cathy Lee-Miller, Dmitry Baturin,Susan P. Fosmire, Susan E. Zelasko, Courtney L. Jones,Jill E. Slansky, Manali Rupji, Bhakti Dwivedi,Curtis J. Henry, and Christopher C. Porter

Significance: This report implicates calcineurin as anintracellular signaling molecule responsible for immuneevasion during leukemia progression and raises the prospectof re-examining IL12 as a therapeutic in leukemia.

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3714 A PolH Transcript with a Short 30UTR EnhancesPolH Expression and Mediates CisplatinResistanceJin Zhang, Wenqiang Sun, Cong Ren,Xiangmudong Kong, Wensheng Yan, and Xinbin Chen

Significance: A short PolH transcript produced byalternative polyadenylation escapes repression by miR-619and confers resistance to cisplatin.

3725 mTORC2 Suppresses GSK3-Dependent SnailDegradation to Positively Regulate Cancer CellInvasion and MetastasisShuo Zhang, Guoqing Qian, Qian-Qian Zhang,Yuying Yao, Dongsheng Wang, Zhuo G. Chen,Li-Jing Wang, Mingwei Chen, and Shi-Yong Sun

Significance: These findings delineate a new regulationmechanism of Snail, an important master regulator ofepithelial–mesenchymal transition and invasion in cancers.

3737 Low-Dose IFNg Induces Tumor Cell Stemness inTumor Microenvironment of Non–Small CellLung CancerMengjia Song, Yu Ping, Kai Zhang, Li Yang, Feng Li,Chaoqi Zhang, Shaoyan Cheng, Dongli Yue,Nomathamsanqa Resegofetse Maimela, Jiao Qu,Shasha Liu, Ting Sun, Zihai Li, Jianchuan Xia, Bin Zhang,Liping Wang, and Yi Zhang

Significance: These findings reveal the dose-dependenteffect of IFNg in inducing tumor stemness and elucidatethe distinct molecular mechanisms activated by IFNg in adose-dependent manner.

3749 Radiation-Induced DNA Damage Cooperateswith Heterozygosity of TP53 and PTEN toGenerate High-Grade GliomasPavlina K. Todorova, Eliot Fletcher-Sananikone,Bipasha Mukherjee, Rahul Kollipara,Vamsidhara Vemireddy, Xian-Jin Xie, Peter M. Guida,Michael D. Story, Kimmo Hatanpaa, Amyn A. Habib,Ralf Kittler, Robert Bachoo, Robert Hromas,John R. Floyd, and Sandeep Burma

Significance: This study uncovers mechanisms by whichionizing radiation, especially particle radiation, promoteGBM development or recurrence.

TRANSLATIONAL SCIENCE

3762 Differential Activity of ATR and WEE1 Inhibitorsin a Highly Sensitive Subpopulation of DLBCLLinked to Replication StressLucy A. Young, Lenka Oplustil O’Connor,Christelle de Renty, Margaret H. Veldman-Jones,Thierry Dorval, Zena Wilson, David R. Jones,Deborah Lawson, Rajesh Odedra,Apolinar Maya-Mendoza, Corinne Reimer, Jiri Bartek,Alan Lau, and Mark J. O’Connor

Significance: ATR and WEE1 inhibitors demonstrateeffective antitumor activity in preclinical models of DLBCLassociated with replication stress, but new mechanisticinsights and biomarkers of response support a differentiatedclinical development strategy.

CONVERGENCE AND TECHNOLOGIES

3776 Patient-Specific Tumor Growth TrajectoriesDetermine Persistent and Resistant Cancer CellPopulations during Treatment with TargetedTherapiesClemens Grassberger, David McClatchy III,Changran Geng, Sophia C. Kamran, Florian Fintelmann,Yosef E. Maruvka, Zofia Piotrowska, Henning Willers,Lecia V. Sequist, Aaron N. Hata, and Harald Paganetti

Significance: These findings quantify preexisting resistanceand persister cell populations, which are essential for theintegration of targeted agents into the management oflocally advanced disease and the timing of radiotherapy inmetastatic patients.

CORRECTION

3789 Correction: ME1 Regulates NADPH Homeostasisto Promote Gastric Cancer Growth andMetastasisYun-Xin Lu, Huai-Qiang Ju, Ze-Xian Liu,Dong-Liang Chen, Yun Wang, Qi Zhao, Qi-Nian Wu,Zhao-lei Zeng, Hai-Bo Qiu, Pei-Shan Hu,Zhi-Qiang Wang, Dong-Sheng Zhang, Feng Wang, andRui-Hua Xu

EDITOR'S NOTES

3790 Editor's Note: MicroRNA-519c SuppressesHypoxia-Inducible Factor-1a Expression andTumor AngiogenesisShih-Ting Cha, Pai-Sheng Chen, Gunnar Johansson,Chia-Yu Chu, Ming-Yang Wang, Yung-Ming Jeng,Sung-Liang Yu, Jin-Shing Chen, King-Jen Chang,Shiou-Hwa Jee, Ching-Ting Tan, Ming-Tsan Lin, andMin-Liang Kuo

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3791 Editor's Note: A Novel Peptide SpecificallyBinding to Interleukin-6 Receptor (gp80)Inhibits Angiogenesis and Tumor GrowthJen-Liang Su, Kuo-Pao Lai, Chi-An Chen,Ching-Yao Yang, Pei-Sheng Chen, Chiao-Chia Chang,Chia-Hung Chou, Chi-Lun Hu, Min-Liang Kuo,Chang-Yao Hsieh, and Lin-Hung Wei

3792 Editor's Note: Connective Tissue Growth FactorConfers Drug Resistance in Breast Cancerthrough Concomitant Up-regulation of Bcl-xLand cIAP1Ming-Yang Wang, Pai-Sheng Chen,Ekambaranellore Prakash, Hsing-Chih Hsu,Hsin-Yi Huang, Ming-Tsan Lin, King-Jen Chang, andMin-Liang Kuo

RETRACTION

3793 Retraction: Knockdown of Contactin-1Expression Suppresses Invasion and Metastasisof Lung AdenocarcinomaJen-Liang Su, Ching-Yao Yang, Jin-Yuan Shih,Lin-Hung Wei, Chang-Yao Hsieh, Yung-Ming Jeng,Ming-Yang Wang, Pan-Chyr Yang, and Min-Liang Kuo

Table of Contents

ABOUT THE COVER

p53 is amajor inducer of apoptosis inmultiple circumstances, including the exposure of cells toproteasome inhibitors. The figure shows the stabilization of p53 in intestinal adenomas ofAPCmin/þ mice treated with proteasome inhibitor bortezomib. Coimmunofluorescent stainingdocumented the colocalization of stabilized p53 (red) with the stem/progenitor cell markerSox9 (blue) and revealed that p53 can be easily stabilized in stem/progenitor-like cells inmouse intestinal adenomas. For details, see article by Xue and colleagues on page 3595.

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