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Cancer Cell
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Dec 11, 2017

Volume 32Issue 6p717-884
Open Archive
On the cover: During acute and chronic inflammation, reactive oxygen species (ROS) are being produced in myeloid and other cells. The release of ROS by inflammatory cells has been suggested to cause cancer by triggering DNA damage in neighboring epithelial cells. The astronauts (ROS) represent volatile ROS molecules such as H2O2 that can easily shuttle between cells (space) and that can interfere with DNA and actively change its structure to induce mutations. For more details, see Canli et al., pp. 869–883. Design by Dirk Stähling....
On the cover: During acute and chronic inflammation, reactive oxygen species (ROS) are being produced in myeloid and other cells. The release of ROS by inflammatory cells has been suggested to cause cancer by triggering DNA damage in neighboring epithelial cells. The astronauts (ROS) represent volatile ROS molecules such as H2O2 that can easily shuttle between cells (space) and that can interfere with DNA and actively change its structure to induce mutations. For more details, see Canli et al., pp. 869–883. Design by Dirk Stähling.
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  • Breaking Down Barriers to Chemoresistance: Role of Chemotherapy-Induced Osteoblastic Jagged1

    • Khalid S. Mohammad,
    • Theresa A. Guise
    Bone metastases are incurable. The bone microenvironment has always been a suspect for this clinical enigma, but the exact mechanisms have been unclear. In this issue of Cancer Cell, Zheng and colleagues provide evidence that chemotherapy itself induces chemoresistance of bone metastases, mediated by osteoblast Jagged1-induced tumor Notch signaling.

  • AML Therapy: Wake Up the Guardian and Cut Loose the Executioners

    • Dario C. Altieri
    In this issue of Cancer Cell, Pan et al. show that a combination therapy designed to reactivate the p53 tumor suppressor while antagonizing the anti-apoptotic function of Bcl-2 is highly active in preclinical models of refractory acute myeloid leukemia (AML). The results may move the needle in this hard-to-treat malignancy.

  • Genomic Biomarkers Predicting Response to Selective CDK4/6 Inhibition: Progress in an Elusive Search

    • Geoffrey I. Shapiro
    In this issue of Cancer Cell, Gong et al. have analyzed the sensitivity of 560 cell lines to the selective CDK4/6 inhibitor abemaciclib and have defined cancers with specific genomic “D-cyclin activating features (DCAF)” as particularly vulnerable. These findings will facilitate patient selection as development of this drug class continues.

  • Stressing Out PanIN: NRF2 Pushes over the Edge

    • Laura Torrente,
    • Gina M. DeNicola
    The mechanisms by which chronic stress promote the development of pancreatic ductal adenocarcinoma (PDAC) are poorly defined. In this issue of Cancer Cell, Todoric et al. discover a role for impaired autophagy in the development of PDAC through p62-mediated activation of NRF2.

  • Glut3 Addiction: A Druggable Vulnerability in Glioblastoma

    • Severa Bunda,
    • Gelareh Zadeh,
    • Kenneth D. Aldape
    The link between GBM molecular subtype and response to treatment remains undefined. In this issue of Cancer Cell, Cosset and colleagues define a subpopulation of patients within the proneural/classical subtype sensitive to integrin blockade because of a Glut3 addiction. These findings reveal context-dependent druggable vulnerability in a subpopulation of GBM.

  • Inflammation, ROS, and Mutagenesis

    • Asmaa El-Kenawi,
    • Brian Ruffell
    It has long been hypothesized that reactive oxygen species (ROS) are responsible for the association between chronic inflammatory diseases and increased tumor incidence. In this issue of Cancer Cell, Canli et al. now demonstrate that amplified ROS production specifically by myeloid cells is sufficient to promote intestinal mutagenesis.

Articles

  • Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

    • Hanqiu Zheng,
    • Yangjin Bae,
    • Sabine Kasimir-Bauer,
    • Rebecca Tang,
    • Jin Chen,
    • Guangwen Ren,
    • Min Yuan,
    • Mark Esposito,
    • Wenyang Li,
    • Yong Wei,
    • Minhong Shen,
    • Lanjing Zhang,
    • Nikolai Tupitsyn,
    • Klaus Pantel,
    • Chadwick King,
    • Jan Sun,
    • Jodi Moriguchi,
    • Helen Toni Jun,
    • Angela Coxon,
    • Brendan Lee,
    • Yibin Kang
    Zheng et al. develop 15D11, a fully human monoclonal antibody to Jagged1, which inhibits Jagged1 on breast cancer cells as well as blocking metastasis-promoting effects of osteoblast-derived Jagged1 induced by chemotherapy. 15D11 reduces bone metastasis and sensitizes metastases to chemotherapy in mouse models of breast cancer.

  • Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy

    • Rongqing Pan,
    • Vivian Ruvolo,
    • Hong Mu,
    • Joel D. Leverson,
    • Gwen Nichols,
    • John C. Reed,
    • Marina Konopleva,
    • Michael Andreeff
    Pan et al. show that p53 activation promotes Mcl-1 degradation, and Bcl-2 inhibition shifts the p53 activation response from G1 arrest to apoptosis. Combining p53 activation and Bcl-2 inhibition overcomes resistance to either alone and provides better therapeutic efficacy in mouse models of acute myeloid leukemia.

  • Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib

    • Xueqian Gong,
    • Lacey M. Litchfield,
    • Yue Webster,
    • Li-Chun Chio,
    • Swee Seong Wong,
    • Trent R. Stewart,
    • Michele Dowless,
    • Jack Dempsey,
    • Yi Zeng,
    • Raquel Torres,
    • Karsten Boehnke,
    • Cecilia Mur,
    • Carlos Marugán,
    • Carmen Baquero,
    • Chunping Yu,
    • Steven M. Bray,
    • Isabella H. Wulur,
    • Chen Bi,
    • Shaoyou Chu,
    • Hui-Rong Qian,
    • Philip W. Iversen,
    • Farhana F. Merzoug,
    • Xiang S. Ye,
    • Christoph Reinhard,
    • Alfonso De Dios,
    • Jian Du,
    • Charles W. Caldwell,
    • María José Lallena,
    • Richard P. Beckmann,
    • Sean G. Buchanan
    Gong et al. identify a subset of cancers highly sensitive to CDK4/6 inhibition, which are characterized by various genomic aberrations known to elevate D-cyclin levels but not by CDKN2A mutations. They also identify a recurrent CCND1 3′UTR mutation associated with increased CCND1 expression in endometrial cancer.

  • Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment

    • Anna H. Turaj,
    • Khiyam Hussain,
    • Kerry L. Cox,
    • Matthew J.J. Rose-Zerilli,
    • James Testa,
    • Lekh N. Dahal,
    • H.T. Claude Chan,
    • Sonya James,
    • Vikki L. Field,
    • Matthew J. Carter,
    • Hyung J. Kim,
    • Jonathan J. West,
    • Lawrence J. Thomas,
    • Li-Zhen He,
    • Tibor Keler,
    • Peter W.M. Johnson,
    • Aymen Al-Shamkhani,
    • Stephen M. Thirdborough,
    • Stephen A. Beers,
    • Mark S. Cragg,
    • Martin J. Glennie,
    • Sean H. Lim
    Turaj et al. test anti-tumor efficacy of immunomodulatory antibodies combined with anti-CD20 and find that anti-CD27/CD20 has a strong benefit in several tumor models. Anti-CD27 induces IFNγ and chemokines in CD8+ T and NK cells, enhancing macrophage infiltration and activation to promote anti-CD20 activity.

  • Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance

    • Shipra Shukla,
    • Joanna Cyrta,
    • Devan A. Murphy,
    • Edward G. Walczak,
    • Leili Ran,
    • Praveen Agrawal,
    • Yuanyuan Xie,
    • Yuedan Chen,
    • Shangqian Wang,
    • Yu Zhan,
    • Dan Li,
    • Elissa W.P. Wong,
    • Andrea Sboner,
    • Himisha Beltran,
    • Juan Miguel Mosquera,
    • Jessica Sher,
    • Zhen Cao,
    • John Wongvipat,
    • Richard P. Koche,
    • Anuradha Gopalan,
    • Deyou Zheng,
    • Mark A. Rubin,
    • Howard I. Scher,
    • Ping Chi,
    • Yu Chen
    Shukla et al. identify an aberrantly expressed gastrointestinal-lineage transcriptome governed by HNF4G and HNF1A in ∼30% of castration-resistant prostate cancer. HNF4G is a pioneer factor for this transcriptional program and its ectopic expression at physiologic levels reduces sensitivity to hormone deprivation.

  • mTORC2 Promotes Tumorigenesis via Lipid Synthesis

    • Yakir Guri,
    • Marco Colombi,
    • Eva Dazert,
    • Sravanth K. Hindupur,
    • Jason Roszik,
    • Suzette Moes,
    • Paul Jenoe,
    • Markus H. Heim,
    • Isabelle Riezman,
    • Howard Riezman,
    • Michael N. Hall
    Guri et al. find that mTORC2 promotes de novo fatty acid and lipid synthesis. This pathway is elevated in human liver cancer and drives hepatosteatosis and liver cancer in mice, whereas its inhibition or deletion of Rictor reduces mouse tumors, suggesting this pathway as a therapeutic target in liver cancer.

  • Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

    • Jelena Todoric,
    • Laura Antonucci,
    • Giuseppe Di Caro,
    • Ning Li,
    • Xuefeng Wu,
    • Nikki K. Lytle,
    • Debanjan Dhar,
    • Sourav Banerjee,
    • Johan B. Fagman,
    • Cecille D. Browne,
    • Atsushi Umemura,
    • Mark A. Valasek,
    • Hannes Kessler,
    • David Tarin,
    • Michael Goggins,
    • Tannishtha Reya,
    • Maria Diaz-Meco,
    • Jorge Moscat,
    • Michael Karin
    Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.

  • MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma

    • Tianzhi Huang,
    • Chung Kwon Kim,
    • Angel A. Alvarez,
    • Rajendra P. Pangeni,
    • Xuechao Wan,
    • Xiao Song,
    • Taiping Shi,
    • Yongyong Yang,
    • Namratha Sastry,
    • Craig M. Horbinski,
    • Songjian Lu,
    • Roger Stupp,
    • John A. Kessler,
    • Ryo Nishikawa,
    • Ichiro Nakano,
    • Erik P. Sulman,
    • Xinghua Lu,
    • Charles David James,
    • Xiao-Ming Yin,
    • Bo Hu,
    • Shi-Yuan Cheng
    Huang et al. show that radiation induces MST4 expression and that MST4 phosphorylates ATG4B at serine 383, which increases ATG4B activity and autophagic flux. Inhibition of ATG4B reduces autophagy and tumorigenicity of glioblastoma (GBM) cells and improves the impact of radiotherapy on GBM growth in mice.

  • Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma

    • Érika Cosset,
    • Sten Ilmjärv,
    • Valérie Dutoit,
    • Kathryn Elliott,
    • Tami von Schalscha,
    • Maria F. Camargo,
    • Alexander Reiss,
    • Toshiro Moroishi,
    • Laetitia Seguin,
    • German Gomez,
    • Jung-Soon Moo,
    • Olivier Preynat-Seauve,
    • Karl-Heinz Krause,
    • Hervé Chneiweiss,
    • Jann N. Sarkaria,
    • Kun-Liang Guan,
    • Pierre-Yves Dietrich,
    • Sara M. Weis,
    • Paul S. Mischel,
    • David A. Cheresh
    Cosset et al. identify a subset of glioblastoma within the proneural and the classical subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression, and are sensitive to agents disrupting the pathway such as cilengitide.

  • Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis

    • Özge Canli,
    • Adele M. Nicolas,
    • Jalaj Gupta,
    • Fabian Finkelmeier,
    • Olga Goncharova,
    • Marina Pesic,
    • Tobias Neumann,
    • David Horst,
    • Martin Löwer,
    • Ugur Sahin,
    • Florian R. Greten
    Canli et al. show that excessive H2O2 produced by myeloid cells, independent of cytokines, transforms intestinal epithelial cells (IEC) by triggering genome-wide DNA mutations. H2O2 also induces IEC to secrete cytokines and chemokines, via a TNFα autocrine loop, to recruit myeloid cells for promotion of tumor invasion.

Correction

  • High-throughput Phenotyping of Lung Cancer Somatic Mutations

    • Alice H. Berger,
    • Angela N. Brooks,
    • Xiaoyun Wu,
    • Yashaswi Shrestha,
    • Candace Chouinard,
    • Federica Piccioni,
    • Mukta Bagul,
    • Atanas Kamburov,
    • Marcin Imielinski,
    • Larson Hogstrom,
    • Cong Zhu,
    • Xiaoping Yang,
    • Sasha Pantel,
    • Ryo Sakai,
    • Jacqueline Watson,
    • Nathan Kaplan,
    • Joshua D. Campbell,
    • Shantanu Singh,
    • David E. Root,
    • Rajiv Narayan,
    • Ted Natoli,
    • David L. Lahr,
    • Itay Tirosh,
    • Pablo Tamayo,
    • Gad Getz,
    • Bang Wong,
    • John Doench,
    • Aravind Subramanian,
    • Todd R. Golub,
    • Matthew Meyerson,
    • Jesse S. Boehm
    (Cancer Cell 30, 214–228; August 8, 2016)
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