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    Transcriptional Regulation of the Warburg Effect in Cancer by SIX1.
    Cancer Cell 2018 Feb 8. Epub 2018 Feb 8.
    Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China. Electronic address:
    Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. Read More

    Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer.
    Cancer Cell 2018 Feb 12. Epub 2018 Feb 12.
    Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. Electronic address:
    Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). Read More

    Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.
    Cancer Cell 2018 Feb;33(2):322-336.e8
    Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, 13353 Berlin, Germany; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Germany.
    Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. Read More

    DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk.
    Cancer Cell 2018 Feb;33(2):309-321.e5
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:
    Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Read More

    Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis.
    Cancer Cell 2018 Feb;33(2):292-308.e7
    Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China. Electronic address:
    Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Read More

    Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.
    Cancer Cell 2018 Feb;33(2):274-291.e8
    Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK. Electronic address:
    Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Read More

    The Integrated Genomic Landscape of Thymic Epithelial Tumors.
    Cancer Cell 2018 Feb;33(2):244-258.e10
    Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA. Electronic address:
    Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. Read More

    Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1.
    Cancer Cell 2018 Feb;33(2):187-201.e10
    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address:
    Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. Read More

    Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations.
    Cancer Cell 2018 Feb;33(2):173-186.e5
    Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02210, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02210, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02210, USA. Electronic address:
    Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Read More

    Cellular Pliancy and the Multistep Process of Tumorigenesis.
    Cancer Cell 2018 Feb;33(2):164-172
    Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe "Cellular Reprogramming and Oncogenesis", Lyon 69008, France.
    Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. Read More

    An Epigenetic Switch: From Senescent Melanocytes to Malignant Melanoma (and Back).
    Cancer Cell 2018 Feb;33(2):162-163
    MRC London Institute of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK; Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK. Electronic address:
    Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators. Read More

    HIPPO Stampede in Nerve Sheath Tumors.
    Cancer Cell 2018 Feb;33(2):160-161
    Albany Medical College, Department of Neuroscience and Experimental Therapeutics, Albany, NY 12208, USA.
    Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth. Read More

    c-Raf in KRas Mutant Cancers: A Moving Target.
    Cancer Cell 2018 Feb;33(2):158-159
    University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. Electronic address:
    Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRas/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling. Read More

    Glycans Pave the Way for Immunotherapy in Triple-Negative Breast Cancer.
    Cancer Cell 2018 Feb;33(2):155-157
    Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina; Laboratorio de Inmuno-Oncología Traslacional, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes 2160, C1428EGA Buenos Aires, Argentina. Electronic address:
    The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment. Read More

    Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery.
    Cancer Cell 2018 Feb;33(2):153-155
    Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
    In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis. Read More

    RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis.
    Cancer Cell 2018 Feb 2;33(2):259-273.e7. Epub 2018 Feb 2.
    Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, 1130 St Nicholas Avenue, ICRC-401B, New York, NY 10032, USA. Electronic address:
    Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Read More

    c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling.
    Cancer Cell 2018 Feb 27;33(2):217-228.e4. Epub 2018 Jan 27.
    Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain. Electronic address:
    A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Read More

    Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma.
    Cancer Cell 2018 Feb 27;33(2):229-243.e4. Epub 2018 Jan 27.
    Departments of Dermatology, and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:
    Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh/Notchsuprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh/Notchbasal cells survive throughout treatment. Read More

    EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma.
    Cancer Cell 2018 Feb 18;33(2):202-216.e6. Epub 2018 Jan 18.
    Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:
    Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. Read More

    Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase.
    Cancer Cell 2018 Jan;33(1):91-107.e6
    Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Hematology and Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address:
    KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Read More

    Molecular Predictors of Gastric Neoplastic Progression.
    Cancer Cell 2018 Jan;33(1):9-11
    St George and Sutherland Clinical School, University of New South Wales, Sydney NSW 2052, Australia. Electronic address:
    In this issue of Cancer Cell, Huang et al. describe comprehensive genetic and epigenetic profiling of gastric intestinal metaplasia lesions from a longitudinal cohort in which outcome data allowed for identification of potential markers of gastric neoplastic progression. Read More

    Characterizing the Killer Colorectal Carcinomas.
    Cancer Cell 2018 Jan;33(1):7-9
    Head, Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:
    In this issue of Cancer Cell, Yaeger et al. report mutations, copy number variations, and selected rearrangements from a large series of metastatic colorectal carcinomas and primaries that produced metastases. The results provide important insights into differences in anatomical site of origin, age at onset, etiologic factors, and therapeutic responses. Read More

    TIM-3 Regulates CD103Dendritic Cell Function and Response to Chemotherapy in Breast Cancer.
    Cancer Cell 2018 Jan;33(1):60-74.e6
    Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive SRB-2, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address:
    Intratumoral CD103dendritic cells (DCs) are necessary for anti-tumor immunity. Here we evaluated the expression of immune regulators by CD103DCs in a murine model of breast cancer and identified expression of TIM-3 as a target for therapy. Anti-TIM-3 antibody improved response to paclitaxel chemotherapy in models of triple-negative and luminal B disease, with no evidence of toxicity. Read More

    What's in a Name? Cell Fate Reprogramming in Sarcomagenesis.
    Cancer Cell 2018 Jan;33(1):5-7
    Departments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Room 3726, Salt Lake City, UT 84112, USA. Electronic address:
    Differentiation features in cancer cells are typically attributed to the cell of origin. In this issue of Cancer Cell, Drummond et al. demonstrate a transdifferentiation program apparent in rhabdomyosarcomas (cancers with skeletal muscle differentiation features) arising through cell fate reprogramming from a single oncogene activation in endothelial cell precursors. Read More

    BET'ing on Dual JAK/BET Inhibition as a Therapeutic Strategy for Myeloproliferative Neoplasms.
    Cancer Cell 2018 Jan;33(1):3-5
    Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address:
    In this issue of Cancer Cell, Kleppe et al. describe a combination strategy designed to inhibit BET bromodomain and JAK/STAT signaling as a method for effectively inhibiting NF-κB and cytokine production in myeloproliferative neoplasms (MPNs). The results provide a strong rationale for clinical evaluation of dual BET/JAK inhibition in MPNs. Read More

    A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia.
    Cancer Cell 2018 Jan;33(1):13-28.e8
    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:
    Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. Read More

    Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer.
    Cancer Cell 2018 Jan;33(1):125-136.e3
    Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Departments of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
    Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Read More

    Hedgehog Pathway Drives Fusion-Negative Rhabdomyosarcoma Initiated From Non-myogenic Endothelial Progenitors.
    Cancer Cell 2018 Jan;33(1):108-124.e5
    Department of Oncology, MS-352, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address:
    Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that histologically resembles embryonic skeletal muscle. RMS occurs throughout the body and an exclusively myogenic origin does not account for RMS occurring in sites devoid of skeletal muscle. We previously described an RMS model activating a conditional constitutively active Smoothened mutant (SmoM2) with aP2-Cre. Read More

    TFIID and MYB Share a Therapeutic Handshake in AML.
    Cancer Cell 2018 Jan;33(1):1-3
    Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC 3052, Australia; Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. Electronic address:
    Selectively disrupting oncogenic transcription factors in cancer remains an elusive ambition of targeted therapeutics. In this issue of Cancer Cell, Xu et al. provide an elegant proof-of-concept study demonstrating that interaction between MYB and the general transcriptional coactivator TFIID can be specifically disrupted to mediate a therapeutic effect in AML. Read More

    Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer.
    Cancer Cell 2018 Jan 28;33(1):137-150.e5. Epub 2017 Dec 28.
    Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore; SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 169856, Singapore; Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore; Singapore Gastric Cancer Consortium, Singapore 119074, Singapore. Electronic address:
    Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We performed (epi)genomic profiling of 138 IMs from 148 cancer-free patients, recruited through a 10-year prospective study. Compared with GCs, IMs exhibit low mutational burdens, recurrent mutations in certain tumor suppressors (FBXW7) but not others (TP53, ARID1A), chromosome 8q amplification, and shortened telomeres. Read More

    Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.
    Cancer Cell 2018 Jan 21;33(1):44-59.e8. Epub 2017 Dec 21.
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
    Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and Nrasexpression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Read More

    β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.
    Cancer Cell 2018 Jan 14;33(1):75-90.e7. Epub 2017 Dec 14.
    Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address:
    Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras;Pdx1-Cre (KC) mice. Read More

    Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms.
    Cancer Cell 2018 Jan 14;33(1):29-43.e7. Epub 2017 Dec 14.
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:
    Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Read More

    Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis.
    Cancer Cell 2017 Dec;32(6):869-883.e5
    Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address:
    Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and senescence. The contribution of individual cell types in the tumor microenvironment to these contrasting effects remains poorly understood. We provide evidence that during intestinal tumorigenesis, myeloid cell-derived HOtriggers genome-wide DNA mutations in intestinal epithelial cells to stimulate invasive growth. Read More

    MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma.
    Cancer Cell 2017 Dec;32(6):840-855.e8
    Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:
    ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Read More

    mTORC2 Promotes Tumorigenesis via Lipid Synthesis.
    Cancer Cell 2017 Dec;32(6):807-823.e12
    Biozentrum, University of Basel, 4056 Basel, Switzerland. Electronic address:
    Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. Read More

    Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib.
    Cancer Cell 2017 Dec;32(6):761-776.e6
    Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address:
    Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. Read More

    Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy.
    Cancer Cell 2017 Dec;32(6):748-760.e6
    Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:
    Evasion of apoptosis is a hallmark of cancer. Bcl-2 and p53 represent two important nodes in apoptosis signaling pathways. We find that concomitant p53 activation and Bcl-2 inhibition overcome apoptosis resistance and markedly prolong survival in three mouse models of resistant acute myeloid leukemia (AML). Read More

    Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy.
    Cancer Cell 2017 Dec;32(6):731-747.e6
    Department of Molecular Biology, Princeton University, Washington Road, LTL 255, Princeton, NJ 08544, USA; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA. Electronic address:
    Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). Read More

    Inflammation, ROS, and Mutagenesis.
    Cancer Cell 2017 Dec;32(6):727-729
    Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address:
    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. Read More

    Glut3 Addiction: A Druggable Vulnerability in Glioblastoma.
    Cancer Cell 2017 Dec;32(6):726-727
    Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. Electronic address:
    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. Read More

    Stressing Out PanIN: NRF2 Pushes over the Edge.
    Cancer Cell 2017 Dec;32(6):723-725
    Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address:
    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. Read More

    Genomic Biomarkers Predicting Response to Selective CDK4/6 Inhibition: Progress in an Elusive Search.
    Cancer Cell 2017 Dec;32(6):721-723
    Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:
    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. Read More

    AML Therapy: Wake Up the Guardian and Cut Loose the Executioners.
    Cancer Cell 2017 Dec;32(6):719-720
    Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address:
    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. Read More

    Breaking Down Barriers to Chemoresistance: Role of Chemotherapy-Induced Osteoblastic Jagged1.
    Cancer Cell 2017 Dec;32(6):717-718
    Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA. Electronic address:
    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. Read More

    Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma.
    Cancer Cell 2017 Dec 30;32(6):856-868.e5. Epub 2017 Nov 30.
    Department of Pathology, Moores Cancer Center, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA. Electronic address:
    While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high-affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the "proneural" and "classical" subtypes that are addicted to aberrant signaling from integrin αvβ3, which activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. Read More

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