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    Enhancing CD8(+) T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy.
    Cancer Cell 2017 Sep;32(3):377-391.e9
    The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address:
    How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8(+) TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8(+) TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8(+) TILs' antigen specificity. Read More

    Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations.
    Cancer Cell 2017 Sep;32(3):360-376.e6
    Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:
    We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. Read More

    A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.
    Cancer Cell 2017 Sep;32(3):342-359.e10
    Department of Pathology and Molecular Pathology, University and University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address:
    Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Read More

    Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma.
    Cancer Cell 2017 Sep;32(3):295-309.e12
    Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:
    We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. Read More

    Intravascular Survival and Extravasation of Tumor Cells.
    Cancer Cell 2017 Sep;32(3):282-293
    Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Ludwigstr. 43, 61231 Bad Nauheim, Germany; J.W. Goethe University Frankfurt, Center for Molecular Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Electronic address:
    Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. Read More

    No Oxygen? No Glucose? No Problem: Fatty Acid Catabolism Enhances Effector CD8(+) TILs.
    Cancer Cell 2017 Sep;32(3):280-281
    Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:
    The tumor microenvironment presents metabolic constraints to immunosurveiling cells. In this issue of Cancer Cell, Zhang et al. demonstrate that CD8(+) TILs reprogram under hypoxic and hypoglycemic conditions, regaining effector function by engaging fatty acid catabolism, which is promoted by fenofibrate and synergistic with immune checkpoint blockade therapy. Read More

    Smoke-Induced Changes to the Epigenome Provide Fertile Ground for Oncogenic Mutation.
    Cancer Cell 2017 Sep;32(3):278-280
    CSIRO Health and Biosecurity, PO Box 52, North Ryde, NSW 1670, Australia.
    How genetic and epigenetic events synergize to generate the oncogenic state is not well understood. In this issue of Cancer Cell, Vaz et al. provide compelling evidence that exposure to chronic cigarette smoke causes progressive epigenetic alterations that prime for key genetic events to drive the development of lung cancer. Read More

    Leukemic Cells "Gas Up" Leaky Bone Marrow Blood Vessels.
    Cancer Cell 2017 Sep;32(3):276-278
    Division of Regenerative Medicine, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:
    In this issue of Cancer Cell, Passaro et al. demonstrate how leukemia through aberrant induction of reactive oxygen species and nitric oxide production trigger marrow vessel leakiness, instigating pro-leukemic function. Disrupted tumor blood vessels promote exhaustion of non-malignant stem and progenitor cells and may facilitate leukemia relapse following chemotherapeutic treatment. Read More

    When LMO1 Meets MYCN, Neuroblastoma Is Metastatic.
    Cancer Cell 2017 Sep;32(3):273-275
    Pediatric Oncology Branch, National Cancer Institute, Center for Cancer Research, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address:
    LMO1 is a high-risk neuroblastoma susceptibility gene, but how LMO1 cooperates with MYCN in neuroblastoma tumorigenesis is unclear. In this issue of Cancer Cell, Zhu et al. develop a novel zebrafish model that elucidates a mechanism by which LMO1 and MYCN synergistically initiate neuroblastoma and contribute to metastatic disease progression. Read More

    Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma.
    Cancer Cell 2017 Sep;32(3):271-273
    Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address:
    In this issue of Cancer Cell, Bosse et al. report GPC2 as a therapeutic target in neuroblastoma. They show that GPC2 is selectively expressed on the cell surface of neuroblastoma and is a dependency in this disease. Read More

    Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia.
    Cancer Cell 2017 Sep 1;32(3):324-341.e6. Epub 2017 Sep 1.
    Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:
    The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Read More

    LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.
    Cancer Cell 2017 Sep 31;32(3):310-323.e5. Epub 2017 Aug 31.
    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
    A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Read More


    Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade.
    Cancer Cell 2017 Aug;32(2):253-267.e5
    Molecular Neurosurgery Laboratory and the Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Department of Neurosurgery, Harvard Medical School, Boston, MA, USA. Electronic address:
    Glioblastoma is an immunosuppressive, fatal brain cancer that contains glioblastoma stem-like cells (GSCs). Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells while inducing anti-tumor immunity. oHSV G47Δ expressing murine IL-12 (G47Δ-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly extended survival of a mouse glioma model. Read More

    Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets.
    Cancer Cell 2017 Aug;32(2):238-252.e9
    Department of Neurosurgery, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; Brain Tumor Center Amsterdam, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, 149 13(th) Street, Charlestown, MA 02129, USA. Electronic address:
    Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0. Read More

    Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma.
    Cancer Cell 2017 Aug;32(2):204-220.e15
    Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:
    Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. Read More

    Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma.
    • Authors:
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    Cancer Cell 2017 Aug;32(2):185-203.e13
    We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. Read More

    Genomic Evolution of Breast Cancer Metastasis and Relapse.
    Cancer Cell 2017 Aug;32(2):169-184.e7
    Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. Electronic address:
    Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Read More

    Control of Metastasis by NK Cells.
    Cancer Cell 2017 Aug;32(2):135-154
    Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA; Université Paris Descartes/Paris V, 75006 Paris, France. Electronic address:
    The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Read More

    A Viro-Immunotherapy Triple Play for the Treatment of Glioblastoma.
    Cancer Cell 2017 08;32(2):133-134
    Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada; Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
    In this issue of Cancer Cell, Saha et al. systematically test and optimize combination therapy strategies in a challenging model of glioblastoma. Durable complete responses were seen only when an oncolytic virus expressing IL12 was coupled with anti-CTLA-4 and anti-PD-1 therapeutics. Read More

    New Views into the Genetic Landscape of Metastatic Breast Cancer.
    Cancer Cell 2017 08;32(2):131-133
    Department of Pathology, Stony Brook Medicine, Stony Brook, NY 11794, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:
    Whether metastasis-specific genetic alterations exist remains controversial. The study by Yates et al. in this issue of Cancer Cell provides evidence that metastases emerge late during primary breast cancer progression and that additional driver mutations are often acquired, posing both challenges and opportunities for precision treatment of metastatic breast cancer. Read More

    Cliques and Schisms of Cancer Genes.
    Cancer Cell 2017 08;32(2):129-130
    Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK. Electronic address:
    With a few exceptions, cancers typically carry more than one driver mutation, sometimes five, ten, or more, and these driver mutations do not necessarily assort randomly. In this issue of Cancer Cell, Mina et al. systematically characterize patterns of co-mutation and mutual exclusivity in 6,456 cancers across 23 tumor types. Read More

    Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure.
    Cancer Cell 2017 Aug 3;32(2):221-237.e13. Epub 2017 Aug 3.
    Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:
    Maintenance of phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that underlies population survival upon stressful exposures. We show that the genomes of a cancer cell subpopulation that survives treatment with otherwise lethal drugs, the drug-tolerant persisters (DTPs), exhibit a repressed chromatin state characterized by increased methylation of histone H3 lysines 9 and 27 (H3K9 and H3K27). We also show that survival of DTPs is, in part, maintained by regulators of H3K9me3-mediated heterochromatin formation and that the observed increase in H3K9me3 in DTPs is most prominent over long interspersed repeat element 1 (LINE-1). Read More

    Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies.
    Cancer Cell 2017 Aug 27;32(2):155-168.e6. Epub 2017 Jul 27.
    Department of Computational Biology, University of Lausanne (UNIL), 1011 Lausanne, Vaud, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. Electronic address:
    Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Read More

    Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology.
    Cancer Cell 2017 Jul;32(1):9-25
    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. Electronic address:
    Small-molecule chemical probes or tools have become progressively more important in recent years as valuable reagents to investigate fundamental biological mechanisms and processes causing disease, including cancer. Chemical probes have also achieved greater prominence alongside complementary biological reagents for target validation in drug discovery. However, there is evidence of widespread continuing misuse and promulgation of poor-quality and insufficiently selective chemical probes, perpetuating a worrisome and misleading pollution of the scientific literature. Read More

    MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.
    Cancer Cell 2017 Jul;32(1):71-87.e7
    Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:
    Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. Read More

    Redefining Hormonal Therapy for Advanced Prostate Cancer: Results from the LATITUDE and CHAARTED Studies.
    Cancer Cell 2017 Jul;32(1):6-8
    University of California, San Francisco, CA, USA. Electronic address:
    Two papers published recently in the New England Journal of Medicine describe the utility of abiraterone acetate, an androgen biosynthesis inhibitor, in the early treatment of metastatic prostate cancer. In addition to establishing a new standard of care, these two articles pose a number of important questions for future investigation. Read More

    Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.
    Cancer Cell 2017 Jul;32(1):42-56.e6
    Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. Electronic address:
    We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4(+) T lymphocytes, and neutrophils in the glioma microenvironment. Read More

    MUC-king with HIF May Rewire Pyrimidine Biosynthesis and Curb Gemcitabine Resistance in Pancreatic Cancer.
    Cancer Cell 2017 07;32(1):3-5
    Ludwig Institute for Cancer Research, New York, NY 10017, USA; The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address:
    In this issue of Cancer Cell, Singh and colleagues report a role for MUC1-induced HIF expression in rewiring ribose synthesis, which drives pyridimine production as a possible resistance mechanism to gemcitabine, adding to complexity and multiple paths to resistance. Read More

    Stabilization of the c-Myc Protein by CAMKIIγ Promotes T Cell Lymphoma.
    Cancer Cell 2017 Jul;32(1):115-128.e7
    Molecular and Cellular Biology of Cancer Program & Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. Electronic address:
    Although high c-Myc protein expression is observed alongside MYC amplification in some cancers, in most cases protein overexpression occurs in the absence of gene amplification, e.g., T cell lymphoma (TCL). Read More

    Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma.
    Cancer Cell 2017 Jul;32(1):101-114.e8
    Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:
    Global transcriptomic imbalance is a ubiquitous feature associated with cancer, including hepatocellular carcinoma (HCC). Analyses of 1,225 clinical HCC samples revealed that a large numbers of RNA binding proteins (RBPs) are dysregulated and that RBP dysregulation is associated with poor prognosis. We further identified that oncogenic activation of a top candidate RBP, negative elongation factor E (NELFE), via somatic copy-number alterations enhanced MYC signaling and promoted HCC progression. Read More

    HDAC Inhibitors Finally Open Up: Chromatin Accessibility Signatures of CTCL.
    Cancer Cell 2017 07;32(1):1-3
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:
    In this issue of Cancer Cell, Qu et al. describe the chromatin accessibility profiles of cutaneous T cell lymphoma, with dynamic assessments of response and resistance to histone deacetylase inhibitor therapy. Their "personal regulome" analysis framework reveals chromatin features that may be predictive of clinical response to epigenetic therapy. Read More

    ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma.
    Cancer Cell 2017 Jul 29;32(1):88-100.e6. Epub 2017 Jun 29.
    Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:
    Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. Read More

    Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.
    Cancer Cell 2017 Jul 22;32(1):57-70.e3. Epub 2017 Jun 22.
    Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:
    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integration of genomics, transcriptomics, and metabolomics. While ICC and HCC share recurrently mutated genes, including TP53, ARID1A, and ARID2, mitotic checkpoint anomalies distinguish the C1 subtype with key drivers PLK1 and ECT2, whereas the C2 subtype is linked to obesity, T cell infiltration, and bile acid metabolism. Read More

    Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors.
    Cancer Cell 2017 Jul 15;32(1):27-41.e4. Epub 2017 Jun 15.
    Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, CCSR 2155c, 269 Campus Drive, Stanford, CA 94305-5168, USA; Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:
    Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4(+) T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Read More

    SnapShot: Immune Checkpoint Inhibitors.
    Cancer Cell 2017 Jun;31(6):848-848.e1
    Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA.
    Immunotherapy has changed the landscape of cancer treatment. Checkpoint blockade therapies unleash breaks in the immune system and induce long-lasting responses. However, a significant number of patients do not respond (innate resistance), and a subset progress after responding (acquired resistance). Read More


    A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis.
    Cancer Cell 2017 Jun;31(6):804-819.e7
    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address:
    Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of α-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Read More

    ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.
    Cancer Cell 2017 Jun;31(6):790-803.e8
    Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA. Electronic address:
    The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. Read More

    Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.
    Cancer Cell 2017 Jun;31(6):771-789.e6
    Institute of Virology, Technische Universität München and Helmholtz Zentrum München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address:
    Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Read More

    MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia.
    Cancer Cell 2017 Jun;31(6):755-770.e6
    Department of Pediatrics, Section of Hematology/Oncology/BMT, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:
    The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Read More

    Intertumoral Heterogeneity within Medulloblastoma Subgroups.
    Cancer Cell 2017 Jun;31(6):737-754.e6
    The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address:
    While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Read More

    Aberrant Glycosylation in Cancer: A Novel Molecular Mechanism Controlling Metastasis.
    Cancer Cell 2017 06;31(6):733-735
    Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal; Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal. Electronic address:
    Glycosylation alterations are involved in several steps of human cancer pathogenesis. In this issue of Cancer Cell, Agrawal et al. identified the glycosyltransferase FUT8 as a previously unrecognized mediator of melanoma metastasis, establishing core fucosylation as a potential therapeutic target for prevention and treatment of metastatic tumors. Read More

    Paradoxical Effects of MLL Paralogs in MLL-Rearranged Leukemia.
    Cancer Cell 2017 06;31(6):729-731
    Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address:
    Conflicting data exist on the requirement for wild-type MLL1 in MLL-rearranged leukemia. In this issue of Cancer Cell, Chen et al. describe complementary approaches demonstrating that MLL1 is dispensable for MLL-fusion-mediated leukemogenesis. Read More

    From One to Many: Further Refinement of Medulloblastoma Subtypes Offers Promise for Personalized Therapy.
    Cancer Cell 2017 06;31(6):727-729
    Section of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Cancer Center, Houston, TX 77030, USA. Electronic address:
    There is significant intertumoral heterogeneity within the four molecular subgroups of medulloblastoma. In this issue of Cancer Cell, Cavalli et al. apply similarity network fusion to gene expression and DNA methylation data to identify 12 medulloblastoma subtypes with distinct molecular and clinical profiles, making an important step toward molecularly tailored therapy. Read More

    Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma.
    Cancer Cell 2017 Jun 25;31(6):833-843.e5. Epub 2017 May 25.
    Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:
    Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). Read More

    Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis.
    Cancer Cell 2017 06 25;31(6):731-733. Epub 2017 May 25.
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
    In this issue of Cancer Cell, Lionakis et al. demonstrate that the combination of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the Bruton tyrosine kinase (BTK) inhibitor ibrutinib induced frequent responses in patients with primary central nervous system lymphoma but was associated with significant toxicity, including pulmonary and cerebral aspergillosis infections. Read More

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