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    2417 results match your criteria Cancer Cell [Journal]

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    Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance.
    Cancer Cell 2017 Nov 3. Epub 2017 Nov 3.
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
    Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. Read More

    Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.
    Cancer Cell 2017 Nov 7. Epub 2017 Nov 7.
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address:
    Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed Kras(G12D) acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. Read More

    SnapShot: Chronic Lymphocytic Leukemia.
    Cancer Cell 2017 Nov;32(5):716-716.e1
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute, Cambridge, MA, USA.
    Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF. Read More

    Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency.
    Cancer Cell 2017 Nov;32(5):701-715.e7
    Section of Molecular Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. Electronic address:
    Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. Read More

    An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression.
    Cancer Cell 2017 Nov;32(5):669-683.e5
    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden. Electronic address:
    Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8(+) T cells. Furthermore, loss of HIF-1α in CD8(+) T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Read More

    Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.
    Cancer Cell 2017 Nov;32(5):654-668.e5
    Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address:
    Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. Read More

    Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis.
    Cancer Cell 2017 Nov;32(5):639-653.e6
    Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Biochemistry, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore. Electronic address:
    Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). Read More

    A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia.
    Cancer Cell 2017 Nov;32(5):608-623.e9
    Centro de Investigación del Cáncer, CSIC - University of Salamanca, 37007 Salamanca, Spain; Instituto de Biología Molecular y Celular del Cáncer, CSIC - University of Salamanca, 37007 Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC - University of Salamanca, 37007 Salamanca, Spain. Electronic address:
    Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. Read More

    Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts.
    Cancer Cell 2017 Nov;32(5):590-607.e4
    Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid, 28029, Spain. Electronic address:
    Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. Read More

    Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer.
    Cancer Cell 2017 Nov;32(5):574-589.e6
    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:
    ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. Read More

    Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure.
    Cancer Cell 2017 Nov;32(5):552-560
    Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
    Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Read More

    Molecular Landscape of Non-Muscle Invasive Bladder Cancer.
    Cancer Cell 2017 Nov;32(5):550-551
    Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:
    In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Read More

    Pontine Infantile Glioma Simplified.
    Cancer Cell 2017 Nov;32(5):548-549
    Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada. Electronic address:
    In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer. Read More

    Does CSF1R Blockade Turn into Friendly Fire?
    Cancer Cell 2017 Nov;32(5):546-547
    Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:
    In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts. Read More

    Early GalNAc O-Glycosylation: Pushing the Tumor Boundaries.
    Cancer Cell 2017 Nov;32(5):544-545
    i3S - Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal; Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal. Electronic address:
    Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14. Read More

    A Two-Faced mSWI/SNF Subunit: Dual Roles for ARID1A in Tumor Suppression and Oncogenicity in the Liver.
    Cancer Cell 2017 Nov;32(5):542-543
    Chemical Biology Program, Harvard University, Cambridge, MA 02138, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA. Electronic address:
    In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit ARID1A in the development and progression of hepatocellular carcinoma (HCC). Read More

    Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival.
    Cancer Cell 2017 Nov;32(5):539-541
    Division of Cancer Research, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland. Electronic address:
    In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif. Read More

    H3.3(K27M) Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas.
    Cancer Cell 2017 Nov 26;32(5):684-700.e9. Epub 2017 Oct 26.
    Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK; Nuclear Function Group, German Centre for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 27, Bonn 53127, Germany. Electronic address:
    Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3(K27M) and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. Read More

    mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability.
    Cancer Cell 2017 Nov 19;32(5):624-638.e5. Epub 2017 Oct 19.
    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:
    The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. Read More

    iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding.
    Cancer Cell 2017 Nov 12;32(5):561-573.e6. Epub 2017 Oct 12.
    School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province 150001, China; Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen 518055, China. Electronic address:
    Reactive oxygen species (ROS) have emerged as important signaling molecules that play crucial roles in carcinogenesis and cytotoxic responses. Nrf2 is the master regulator of ROS balance. Thus, uncovering mechanisms of Nrf2 regulation is important for the development of alternative treatment strategies for cancers. Read More

    Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML.
    Cancer Cell 2017 Oct;32(4):506-519.e5
    Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:
    Chimeric antigen receptor (CAR) therapy targeting CD19 has yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for overexpressed molecules with tolerable systemic expression. We integrated large transcriptomics and proteomics datasets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34(+)CD38(-) hematopoietic cells, T cells, or vital tissues. Read More

    Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia.
    Cancer Cell 2017 Oct;32(4):490-505.e10
    Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:
    The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. Read More

    Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling.
    Cancer Cell 2017 Oct;32(4):474-489.e6
    Department of Medicine, University of Washington, Seattle, WA, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA; Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA, USA. Electronic address:
    Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. Read More

    A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.
    Cancer Cell 2017 Oct;32(4):460-473.e6
    Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:
    The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53(53,54) TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Read More

    Mitotic Spindle Assembly and Genomic Stability in Breast Cancer Require PI3K-C2α Scaffolding Function.
    Cancer Cell 2017 Oct;32(4):444-459.e7
    Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin 10126, Italy. Electronic address:
    Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase α (PI3K-C2α) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2α causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2α expression is required for genomic stability. Read More

    Microenvironment-Driven Shift of Cohesion/Detachment Balance within Tumors Induces a Switch toward Metastasis in Neuroblastoma.
    Cancer Cell 2017 Oct;32(4):427-443.e8
    University of Lyon, University of Lyon 1 Claude Bernard Lyon1, NeuroMyoGene Institute, CNRS UMR5310, INSERM U1217, 16 rue Raphael Dubois, F-69000 Lyon, France. Electronic address:
    Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. Disseminated forms have high frequency of multiple tumoral foci whose etiology remains unknown; NB embryonic origin limits investigations in patients and current models. We developed an avian embryonic model driving human NB tumorigenesis in tissues homologous to patients. Read More

    The Stromal Niche for Epithelial Stem Cells: A Template for Regeneration and a Brake on Malignancy.
    Cancer Cell 2017 Oct;32(4):404-410
    Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:
    Stromal restraint of cancer growth and progression-emerging as a widespread phenomenon in epithelial cancers such as bladder, pancreas, colon, and prostate-appears rooted in stromal cell niche activity. During normal tissue repair, stromal niche signals, often Hedgehog-induced, promote epithelial stem cell differentiation as well as self-renewal, thus specifying a regenerating epithelial pattern. In the case of cancerous tissue, stromal cell-derived differentiation signals in particular may provide a brake on malignant growth. Read More

    Apoptosis, Up the Ante.
    Cancer Cell 2017 Oct;32(4):402-403
    Department of Pathology, Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address:
    The clinical success of the BH3-mimetic venetoclax has generated increasing interest to target BCL2 family proteins in oncology. In this issue of Cancer Cell, Reyna and colleagues demonstrate the potential of a pharmacological activator of the pro-apoptotic protein BAX to suppress acute myeloid leukemia both alone and together with venetoclax. Read More

    Cellular Origin of Androgen Receptor Pathway-Independent Prostate Cancer and Implications for Therapy.
    Cancer Cell 2017 Oct;32(4):399-401
    Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center (SKCCC), The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address:
    In this issue of Cancer Cell, Bluemn et al. report that ∼20% of metastatic castration-resistant prostate cancers express neither AR nor neuroendocrine genes and show AR pathway-independent growth, driven instead by a FGFR/MAPK/ID1 signaling cascade. These results provide a strong rationale for co-targeting AR bypass pathways with initial AR antagonism. Read More

    Tumor Suppression by p53: Bring in the Hippo!
    Cancer Cell 2017 Oct;32(4):397-399
    Department of Molecular Cell Biology, The Weizmann Institute, Rehovot 76100, Israel. Electronic address:
    In this issue of Cancer Cell, Mello et al. investigated how p53 suppresses pancreatic cancer and discovered a key role for the tyrosine phosphatase PTPN14, a p53 transcriptional target. PTPN14 restrains YAP, curbing its potential oncogenic effects. Read More

    Neuroblastoma Metastases: Leveraging the Avian Neural Crest.
    Cancer Cell 2017 Oct;32(4):395-397
    Departments of Neurology, Pediatrics, and Neurosurgery, Brain Tumor Research Center, University of California, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA. Electronic address:
    Neuroblastoma, an embryonal cancer of neural crest origin, shows metastases frequently at diagnosis. In this issue of Cancer Cell, Delloye-Bourgeois and colleagues demonstrate that neuroblastoma cell lines and patient-derived xenografts engraft and adopt a metastatic program in chick embryos. They identify Sema3C as a candidate switch that regulates metastatic spread. Read More

    Exploiting the Hidden Treasure of Detained Introns.
    Cancer Cell 2017 Oct;32(4):393-395
    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA. Electronic address:
    Many mammalian genes contain poorly spliced introns, resulting in nuclear detention of partially spliced transcripts, which may be exploited to modulate gene expression. In this issue of Cancer Cell, Braun et al. report that the arginine methyltransferase PRMT5 is critical for tumor cell proliferation by regulating numerous detained introns. Read More

    Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma.
    Cancer Cell 2017 Oct 28;32(4):411-426.e11. Epub 2017 Sep 28.
    The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address:
    Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. Read More

    Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.
    Cancer Cell 2017 Oct 28;32(4):520-537.e5. Epub 2017 Sep 28.
    Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK. Electronic address:
    We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3. Read More


    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 09;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 09;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 09;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 09;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 09;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


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