2,537 results match your criteria Cancer Cell [Journal]


Epigenetic ConFUSION: SS18-SSX Fusion Rewires BAF Complex to Activate Bivalent Genes in Synovial Sarcoma.

Cancer Cell 2018 Jun;33(6):951-953

Simpson Querrey Center for Epigenetics, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 320 E. Superior St., Chicago, IL 60611, USA. Electronic address:

In this issue of Cancer Cell, McBride and colleagues report that the synovial sarcoma SS18-SSX fusion drives BAF complex recruitment to bivalent domains repressed by PRC2 complex to orchestrate aberrant transcriptional activation. Redistribution of BAF localization is a major driver of synovial sarcoma proliferation and presents a promising therapeutic target. Read More

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ROS Promotes Cancer Cell Survival through Calcium Signaling.

Cancer Cell 2018 Jun;33(6):949-951

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

To avoid reactive oxygen species (ROS)-induced cell death, cancer cells increase their antioxidant defense system. In this issue of Cancer Cell, Takahashi et al. identify a novel, non-canonical oxidative stress defense mechanism involving TRPA1, a redox-sensitive Ca channel, and the upregulation of anti-apoptotic pathways to promote cancer cell survival. Read More

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CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis.

Cancer Cell 2018 Jun;33(6):1111-1127.e5

Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address:

Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Read More

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June 2018
1 Read

Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.

Cancer Cell 2018 Jun;33(6):1078-1093.e12

Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern 3012, Switzerland. Electronic address:

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. Read More

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Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling.

Cancer Cell 2018 Jun;33(6):1061-1077.e6

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Moores Cancer Center, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA. Electronic address:

How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Read More

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Th9 Cells Represent a Unique Subset of CD4 T Cells Endowed with the Ability to Eradicate Advanced Tumors.

Cancer Cell 2018 Jun;33(6):1048-1060.e7

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

The antitumor effector T helper 1 (Th1) and Th17 cells represent two T cell paradigms: short-lived cytolytic Th1 cells and "stem cell-like" memory Th17 cells. We report that Th9 cells represent a third paradigm-they are less-exhausted, fully cytolytic, and hyperproliferative. Only tumor-specific Th9 cells completely eradicated advanced tumors, maintained a mature effector cell signature with cytolytic activity as strong as Th1 cells, and persisted as long as Th17 cells in vivo. Read More

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Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens.

Cancer Cell 2018 Jun;33(6):1033-1047.e5

Agenus Inc., Lexington, MA 02421, USA. Electronic address:

The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). Read More

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Non-conventional Inhibitory CD4Foxp3PD-1 T Cells as a Biomarker of Immune Checkpoint Blockade Activity.

Cancer Cell 2018 Jun;33(6):1017-1032.e7

Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4Foxp3 T cells expressing PD-1 (4PD1) and observed that 4PD1 accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1 increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. Read More

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BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation.

Cancer Cell 2018 Jun;33(6):1004-1016.e5

Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, 1365C Clifton Road N.E, C5078, Atlanta, GA 30322, USA; Department of Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address:

Adhesion G protein-coupled receptors (ADGRs) encompass 33 human transmembrane proteins with long N termini involved in cell-cell and cell-matrix interactions. We show the ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in medulloblastomas (MBs) through a methyl-CpG binding protein MBD2-dependent mechanism. Knockout of Adgrb1 in mice augments proliferation of cerebellar granule neuron precursors, and leads to accelerated tumor growth in the Ptch1 transgenic MB mouse model. Read More

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June 2018
1 Read

The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma.

Cancer Cell 2018 Jun 31;33(6):1128-1141.e7. Epub 2018 May 31.

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Read More

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June 2018
1 Read

Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells.

Cancer Cell 2018 Jun 24;33(6):1094-1110.e8. Epub 2018 May 24.

Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona 08028, Spain; ICREA, Pg. Lluís Companys 23, Barcelona 08010, Spain. Electronic address:

Breast cancer is the second leading cause of cancer-related death among women. Here we report a role for the protein kinase p38α in coordinating the DNA damage response and limiting chromosome instability during breast tumor progression, and identify the DNA repair regulator CtIP as a p38α substrate. Accordingly, decreased p38α signaling results in impaired ATR activation and homologous recombination repair, with concomitant increases in replication stress, DNA damage, and chromosome instability, leading to cancer cell death and tumor regression. Read More

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Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance.

Cancer Cell 2018 Jun 24;33(6):985-1003.e7. Epub 2018 May 24.

Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Cancer cell survival is dependent on oxidative-stress defenses against reactive oxygen species (ROS) that accumulate during tumorigenesis. Here, we show a non-canonical oxidative-stress defense mechanism through TRPA1, a neuronal redox-sensing Ca-influx channel. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 is critical for survival of inner cells that exhibit ROS accumulation. Read More

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Biological Role and Therapeutic Potential of IDH Mutations in Cancer.

Cancer Cell 2018 May 14. Epub 2018 May 14.

Department of Pathology, Duke University, Durham, NC, USA; The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA. Electronic address:

Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. Read More

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Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade.

Cancer Cell 2018 May;33(5):922-936.e10

Merus NV, 3584 Utrecht, the Netherlands. Electronic address:

HER2-driven cancers require phosphatidylinositide-3 kinase (PI3K)/Akt signaling through HER3 to promote tumor growth and survival. The therapeutic benefit of HER2-targeting agents, which depend on PI3K/Akt inhibition, can be overcome by hyperactivation of the heregulin (HRG)/HER3 pathway. Here we describe an unbiased phenotypic combinatorial screening approach to identify a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. Read More

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May 2018
5 Reads

The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma.

Cancer Cell 2018 May;33(5):905-921.e5

Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address:

Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3α/β signaling pathway, which upregulates glutaminolysis. Read More

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May 2018
6 Reads

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial.

Cancer Cell 2018 May;33(5):829-842.e5

Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK. Electronic address:

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8 tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Read More

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May 2018
1 Read

A Convergence-Based Framework for Cancer Drug Resistance.

Cancer Cell 2018 May;33(5):801-815

Eli Lilly and Company, Indianapolis, IN 46225, USA.

Despite advances in cancer biology and therapeutics, drug resistance remains problematic. Resistance is often multifactorial, heterogeneous, and prone to undersampling. Nonetheless, many individual mechanisms of targeted therapy resistance may coalesce into a smaller number of convergences, including pathway reactivation (downstream re-engagement of original effectors), pathway bypass (recruitment of a parallel pathway converging on the same downstream output), and pathway indifference (development of a cellular state independent of the initial therapeutic target). Read More

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It's ALL in the Family: IKZF1 and Hereditary Leukemia.

Cancer Cell 2018 May;33(5):798-800

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA. Electronic address:

IKZF1 plays an essential role in lymphopoiesis, and somatic IKZF1 variants in acute lymphoblastic leukemia (ALL) are associated with poor prognosis. In this issue of Cancer Cell, Churchman et al. add to the list of leukemia predisposition genes with the identification and characterization of germline IKZF1 variants in childhood ALL. Read More

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Targeting Therapy Resistance: When Glutamine Catabolism Becomes Essential.

Cancer Cell 2018 May;33(5):795-797

Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. Electronic address:

Identifying contexts in which cancer cells become addicted to specific nutrients is critical for developing targeted metabolic therapies. In this issue of Cancer Cell, Momcilovic et al. report that suppressed glycolysis following mTOR inhibition is countered by adaptive glutamine catabolism in lung squamous cell carcinoma, sensitizing tumors to glutaminase inhibition. Read More

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Targeting the (Un)differentiated State of Cancer.

Cancer Cell 2018 May;33(5):793-795

Cutaneous Biology Research Center, Department of Dermatology and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Dedifferentation in cancer is associated with intrinsic and acquired resistance to therapies. In this issue of Cancer Cell, Tsoi et al. identify four differentiation states in melanoma and provide evidence that melanoma cells develop drug resistance through a stepwise dedifferentiation process, making them vulnerable to ferroptotic cell death-inducing compounds. Read More

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Genomic Features of Response to Combination Immunotherapy in Lung Cancer.

Cancer Cell 2018 May;33(5):791-793

Department of Medical Oncology, University Hospital of Lausanne (CHUV), 1011 Lausanne, Switzerland. Electronic address:

In this issue of Cancer Cell, Hellmann et al. describe in two clinical trials the importance of tumor mutational burden as an independent predictive marker for outcomes with combination nivolumab plus ipilimumab as first-line therapy in metastatic non-small-cell lung cancer and in relapsed small-cell lung cancer. Read More

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May 2018
1 Read

A-to-I RNA Editing: An Overlooked Source of Cancer Mutations.

Cancer Cell 2018 May;33(5):789-790

The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel. Electronic address:

RNA editing is a source of transcriptomic diversity, mainly in non-coding regions, and is found to be altered in cancer. In this issue of Cancer Cell, Peng et al. show that RNA editing events are manifested at the proteomic levels and are a source of cancer protein heterogeneity. Read More

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May 2018
5 Reads

CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought.

Cancer Cell 2018 Apr 10. Epub 2018 Apr 10.

The Louis V. Gerstner Graduate School of Biomedical Sciences and the Sloan Kettering Institute Program in Molecular Biology, Memorial Sloan Kettering Cancer Center, RRL917C, Box 207, 1275 York Avenue, New York, NY 10065, USA. Electronic address:

CDK4/6 inhibitors are among a new generation of therapeutics. Building upon the striking success of the combination of CDK4/6 inhibitors and the hormone receptor antagonist letrozole in breast cancer, many other combinations have recently entered clinical trials in multiple diseases. To achieve maximal benefit with CDK4/6 inhibitors it will be critical to understand the cellular mechanisms by which they act. Read More

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April 2018
1 Read

Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer.

Cancer Cell 2018 May 3;33(5):853-861.e4. Epub 2018 May 3.

Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

Durable responses and encouraging survival have been demonstrated with immune checkpoint inhibitors in small-cell lung cancer (SCLC), but predictive markers are unknown. We used whole exome sequencing to evaluate the impact of tumor mutational burden on efficacy of nivolumab monotherapy or combined with ipilimumab in patients with SCLC from the nonrandomized or randomized cohorts of CheckMate 032. Patients received nivolumab (3 mg/kg every 2 weeks) or nivolumab plus ipilimumab (1 mg/kg plus 3 mg/kg every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks). Read More

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May 2018
5 Reads

NRF2 and the Hallmarks of Cancer.

Cancer Cell 2018 Apr 5. Epub 2018 Apr 5.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA. Electronic address:

The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. Read More

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Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells.

Cancer Cell 2018 May 26;33(5):862-873.e5. Epub 2018 Apr 26.

Department of Cell Biology, The University of Miami Miller School of Medicine, University of Miami, 511 Papanicolaou Building, 1550 NW 10th Avenue, Miami, FL 33136, USA. Electronic address:

The ability of dying cells to activate antigen-presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here, we show that engulfed cells containing cytosolic double-stranded DNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs via extrinsic STING (stimulator of interferon genes) signaling, to promote antigen cross-presentation. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans. Read More

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A-to-I RNA Editing Contributes to Proteomic Diversity in Cancer.

Cancer Cell 2018 May 26;33(5):817-828.e7. Epub 2018 Apr 26.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes. However, due to the complexity of post-transcriptional regulation, the contribution of RNA editing to proteomic diversity in human cancers remains unclear. Here, we performed an integrated analysis of TCGA genomic data and CPTAC proteomic data. Read More

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May 2018
11 Reads

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.

Cancer Cell 2018 May 19;33(5):874-889.e7. Epub 2018 Apr 19.

Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of Cambridge and Wellcome Trust-MRC Stem Cell Institute, Hills Road, Cambridge CB2 0AN, UK. Electronic address:

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2 oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Read More

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May 2018
1 Read

Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia.

Cancer Cell 2018 May 19;33(5):937-948.e8. Epub 2018 Apr 19.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0. Read More

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May 2018
7 Reads

The Platelet Lifeline to Cancer: Challenges and Opportunities.

Cancer Cell 2018 Jun 12;33(6):965-983. Epub 2018 Apr 12.

Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Besides their function in limiting blood loss and promoting wound healing, experimental evidence has highlighted platelets as active players in all steps of tumorigenesis including tumor growth, tumor cell extravasation, and metastasis. Additionally, thrombocytosis in cancer patients is associated with adverse patient survival. Due to the secretion of large amounts of microparticles and exosomes, platelets are well positioned to coordinate both local and distant tumor-host crosstalk. Read More

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June 2018
3 Reads

Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress.

Cancer Cell 2018 May 12;33(5):890-904.e5. Epub 2018 Apr 12.

Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 570 Westwood Plaza, Building 114, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA. Electronic address:

Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Read More

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May 2018
2 Reads

Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

Cancer Cell 2018 May 12;33(5):843-852.e4. Epub 2018 Apr 12.

Department of Medicine, Memorial Sloan Kettering Cancer Center, 885 2(nd) Avenue, New York, NY 10017, USA; Weill Cornell School of Medicine, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. Read More

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May 2018
4 Reads

The Intestinal Microbiota in Colorectal Cancer.

Cancer Cell 2018 Jun 12;33(6):954-964. Epub 2018 Apr 12.

Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria; Christian Doppler Laboratory of Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria.

Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Read More

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June 2018
1 Read

Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor.

Cancer Cell 2018 Apr;33(4):770-784.e6

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

Obesity is a leading risk factor for cancer. However, understanding the crosstalk between adipocytes and tumor cells in vivo, independently of dietary contributions, is a major gap in the field. Here we used a prostate cancer (PCa) mouse model in which the signaling adaptor p62/Sqstm1 is selectively inactivated in adipocytes. Read More

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April 2018
1 Read

Molecular Signatures of Regression of the Canine Transmissible Venereal Tumor.

Cancer Cell 2018 Apr;33(4):620-633.e6

Department of Infection, Division of Infection & Immunity, University College London (UCL), Cruciform Building, 90 Gower Street, London WC1E 6BT, UK. Electronic address:

The canine transmissible venereal tumor (CTVT) is a clonally transmissible cancer that regresses spontaneously or after treatment with vincristine, but we know little about the regression mechanisms. We performed global transcriptional, methylation, and functional pathway analyses on serial biopsies of vincristine-treated CTVTs and found that regression occurs in sequential steps; activation of the innate immune system and host epithelial tissue remodeling followed by immune infiltration of the tumor, arrest in the cell cycle, and repair of tissue damage. We identified CCL5 as a possible driver of CTVT regression. Read More

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April 2018
1 Read

The Origins and Vulnerabilities of Two Transmissible Cancers in Tasmanian Devils.

Cancer Cell 2018 Apr;33(4):607-619.e15

Transmissible Cancer Group, Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. Electronic address:

Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. Although rare in nature, two facial tumor clones affect Tasmanian devils. Here we perform comparative genetic and functional characterization of these lineages. Read More

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April 2018
2 Reads

Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines.

Cancer Cell 2018 Apr;33(4):599-605

Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Selective destruction of neoplastic tissues by oncolytic viruses (OVs) leads to antigen-agnostic boosting of neoantigen-specific cytotoxic T lymphocyte (CTL) responses, making OVs ideal companions for checkpoint blockade therapy. Here we discuss the mechanisms whereby OVs modulate both adjuvanticity and antigenicity of tumor cells. Suppression of antitumor immunity after OV therapy has not been observed, possibly because viral antigen expression diminishes as the antiviral response matures, thereby progressively honing the CTL response to tumor neoantigens. Read More

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April 2018
4 Reads

Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies.

Cancer Cell 2018 Apr;33(4):581-598

Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

Checkpoint blockade has formally demonstrated that reactivating anti-tumor immune responses can regress tumors. However, this only occurs in a fraction of patients. Incorporating these therapies in more powerful combinations is thus a logical next step. Read More

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April 2018
7 Reads

The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy.

Cancer Cell 2018 Apr;33(4):570-580

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit Number 1484, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Unit 1954, 1881 East Road, Houston, Texas 77054, USA. Electronic address:

The microbiome is receiving significant attention given its influence on a host of human diseases including cancer. Its role in response to cancer treatment is becoming increasingly apparent, with evidence suggesting that modulating the gut microbiome may affect responses to numerous forms of cancer therapy. A working knowledge of the microbiome is vital as we move forward in this age of precision medicine, and an understanding of the microbiome's influence on immune responses and cancer is key. Read More

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April 2018
1 Read

The Immune Revolution: A Case for Priming, Not Checkpoint.

Cancer Cell 2018 Apr;33(4):563-569

Abramson Cancer Center, University of Pennsylvania, 12 Floor South Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Electronic address:

Most tumors are unresponsive to immune checkpoint blockade, especially if deep immunosuppression in the tumor develops prior to and prevents T cell immunosurveillance. Failed or frustrated T cell priming often needs repair before successful sensitization to PD-1/PD-L1 blockade. CD40 activation plays a critical role in generating T cell immunity, by activating dendritic cells, and converting cold tumors to hot. Read More

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April 2018
2 Reads

T Cell Dysfunction in Cancer.

Cancer Cell 2018 Apr;33(4):547-562

Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Read More

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April 2018
1 Read

More Rules, Still Exceptions: Understanding Immunomodulatory Antibody Activity In Vivo.

Cancer Cell 2018 Apr;33(4):545-546

Institute of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erwin-Rommelstr. 3, 91058 Erlangen, Germany; Medical Immunology Campus Erlangen, University of Erlangen-Nürnberg, Erwin-Rommelstr. 3, 91058 Erlangen, Germany. Electronic address:

Understanding how agonistic and checkpoint control antibodies mediate their activity in vivo is essential for further development of these promising anti-cancer therapies. In this issue of Cancer Cell, studies by Vargas et al. and Yu et al. Read More

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April 2018
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Mechanistic Insights into Transmissible Cancers of Mammals.

Cancer Cell 2018 Apr;33(4):543-544

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. In this issue of Cancer Cell, two articles by Stammnitz et al. and Frampton et al. Read More

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April 2018
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Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.

Cancer Cell 2018 Apr 2;33(4):721-735.e8. Epub 2018 Apr 2.

Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address:

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. Read More

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April 2018
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lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer.

Cancer Cell 2018 Apr 2;33(4):706-720.e9. Epub 2018 Apr 2.

Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address:

We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Read More

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April 2018
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A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers.

Cancer Cell 2018 Apr 2;33(4):690-705.e9. Epub 2018 Apr 2.

Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Read More

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April 2018
12 Reads

Genomic and Functional Approaches to Understanding Cancer Aneuploidy.

Cancer Cell 2018 Apr 2;33(4):676-689.e3. Epub 2018 Apr 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Cancer Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Department of Pathology, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address:

Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Read More

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April 2018
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Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer.

Cancer Cell 2018 Apr 29;33(4):752-769.e8. Epub 2018 Mar 29.

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, 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:

Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Read More

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April 2018
3 Reads