2,690 results match your criteria Cancer Cell [Journal]


Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.

Cancer Cell 2019 Apr;35(4):677-691.e10

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

FTO, an mRNA N-methyladenosine (mA) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's mA demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108193015
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http://dx.doi.org/10.1016/j.ccell.2019.03.006DOI Listing
April 2019
14 Reads

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias.

Cancer Cell 2019 Apr;35(4):664-676.e7

Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address:

Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.03.004DOI Listing

γ-Catenin-Dependent Signals Maintain BCR-ABL1 B Cell Acute Lymphoblastic Leukemia.

Cancer Cell 2019 Apr;35(4):649-663.e10

Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland. Electronic address:

The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1 B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.03.005DOI Listing
April 2019
1 Read

Doomed from the TERT? A Two-Stage Model of Tumorigenesis in IDH-Wild-Type Glioblastoma.

Cancer Cell 2019 Apr;35(4):542-544

The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA. Electronic address:

Using longitudinal molecular profiling, Körber et al. propose in this issue of Cancer Cell that IDH-wild-type glioblastomas initiate years pre-diagnosis with chromosome-level alterations that drive cell proliferation but require survival-promoting mutations, commonly in the TERT promoter, to form a detectable tumor. Multiple subclones drive disease progression, creating a therapeutic challenge. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108193015
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http://dx.doi.org/10.1016/j.ccell.2019.03.009DOI Listing
April 2019
1 Read

The Yin and Yang of RNA Methylation: An Imbalance of Erasers Enhances Sensitivity to FTO Demethylase Small-Molecule Targeting in Leukemia Stem Cells.

Cancer Cell 2019 Apr;35(4):540-541

Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address:

A prevalent eukaryotic N-methyladensosine (mA) post-transcriptional mark can be "erased" by the mA demethylase FTO, which is commonly deregulated in acute myeloid leukemia (AML). In this issue of Cancer Cell, Huang et al. design small-molecule FTO inhibitors, FB23 and FB23-2, and demonstrate their potent inhibitory impact in AML models. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108193015
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http://dx.doi.org/10.1016/j.ccell.2019.03.011DOI Listing
April 2019
2 Reads

Deciphering Macrophage and Monocyte Code to Stratify Human Breast Cancer Patients.

Authors:
Vincenzo Bronte

Cancer Cell 2019 Apr;35(4):538-539

Department of Medicine, University of Verona, Policlinico GB Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy. Electronic address:

In this issue of Cancer Cell, Cassetta et al. present a detailed analysis of the transcriptional profile imprinted on monocytes and macrophages by human breast and endometrial cancers, proposing SIGLEC1 and CCL8 as novel biomarkers in tumor-associated macrophages for breast cancer patient stratification and prognosis. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.03.010DOI Listing

Oncogenic KRAS Drives Immune Suppression in Colorectal Cancer.

Cancer Cell 2019 Apr;35(4):535-537

Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. Electronic address:

In this issue of Cancer Cell, Liao et al. demonstrate that oncogenic KRAS drives an immune suppressive program in colorectal cancer by repressing IRF2 expression, which leads to downregulation of interferon responsive genes, enhanced expression of CXCL3 and recruitment of suppressive myeloid cells, and subsequent resistance to immune checkpoint blockade. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.03.008DOI Listing
April 2019
1 Read

Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.

Cancer Cell 2019 Apr 8;35(4):573-587.e6. Epub 2019 Apr 8.

Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain. Electronic address:

Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.03.002DOI Listing
April 2019
1 Read

Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties.

Cancer Cell 2019 Apr 4;35(4):633-648.e7. Epub 2019 Apr 4.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address:

UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.03.003DOI Listing

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.

Cancer Cell 2019 Apr 28;35(4):603-617.e8. Epub 2019 Mar 28.

Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467783PMC
April 2019
1 Read
23.523 Impact Factor

Intraclonal Plasticity in Mammary Tumors Revealed through Large-Scale Single-Cell Resolution 3D Imaging.

Cancer Cell 2019 Apr 28;35(4):618-632.e6. Epub 2019 Mar 28.

Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address:

Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108193010
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http://dx.doi.org/10.1016/j.ccell.2019.02.010DOI Listing
April 2019
2 Reads

Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets.

Cancer Cell 2019 Apr 28;35(4):588-602.e10. Epub 2019 Mar 28.

MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York 10461, USA. Electronic address:

The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472943PMC
April 2019
1 Read
23.523 Impact Factor

Evolutionary Trajectories of IDH Glioblastomas Reveal a Common Path of Early Tumorigenesis Instigated Years ahead of Initial Diagnosis.

Cancer Cell 2019 Apr 21;35(4):692-704.e12. Epub 2019 Mar 21.

Division of Molecular Genetics, German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

We studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response for isocitrate dehydrogenase (IDH)-wild-type glioblastoma, a rapidly regrowing tumor. We inferred the evolutionary trajectories of matched pairs of primary and relapsed tumors based on deep whole-genome-sequencing data. This analysis suggests both a distant origin of de novo glioblastoma, up to 7 years before diagnosis, and a common path of early tumorigenesis, with one or more of chromosome 7 gain, 9p loss, or 10 loss, at tumor initiation. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108193010
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http://dx.doi.org/10.1016/j.ccell.2019.02.007DOI Listing
April 2019
1 Read
23.523 Impact Factor

KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer.

Cancer Cell 2019 Apr 21;35(4):559-572.e7. Epub 2019 Mar 21.

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

The biological functions and mechanisms of oncogenic KRAS (KRAS) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467776PMC
April 2019
2 Reads
23.523 Impact Factor

Waun Ki Hong (1942-2019) John Mendelsohn (1936-2019).

Cancer Cell 2019 Feb 11;35(2):157-160. Epub 2019 Feb 11.

Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, CA.

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http://dx.doi.org/10.1016/j.ccell.2019.01.014DOI Listing
February 2019

DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors.

Cancer Cell 2019 Mar;35(3):519-533.e8

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK. Electronic address:

Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, only 15%-20% of ovarian cancers harbor BRCA mutations, therefore additional therapies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are sensitive to a poly(ADP-ribose) glycohydrolase (PARG) inhibitor. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428690PMC
March 2019
1 Read

Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting.

Cancer Cell 2019 Mar;35(3):489-503.e8

Program in Immunology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D3-100, Seattle, WA 98109-1024, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA.

Many potential targets for CAR-T cells in solid tumors are expressed in some normal tissues, raising concern for off-tumor toxicity. Following lymphodepletion, CAR-T cells targeting the tumor-associated antigen ROR1 lysed tumors in mice but induced lethal bone marrow failure due to recognition of ROR1 stromal cells. To improve selectivity, we engineered T cells with synthetic Notch (synNotch) receptors specific for EpCAM or B7-H3, which are expressed on ROR1 tumor cells but not ROR1 stromal cells. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450658PMC
March 2019
1 Read

CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response.

Cancer Cell 2019 Mar;35(3):473-488.e6

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Chimeric antigen receptor (CAR) T cells provide great efficacy in B cell malignancies. However, improved CAR T cell therapies are still needed. Here, we engineered tumor-targeted CAR T cells to constitutively express the immune-stimulatory molecule CD40 ligand (CD40L) and explored efficacy in different mouse leukemia/lymphoma models. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428219PMC
March 2019
1 Read

Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways.

Cancer Cell 2019 Mar;35(3):441-456.e8

Research Department of Pathology, Cancer Institute, University College London, London WC1E 6BT, UK; Department of Cellular and Molecular Pathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK. Electronic address:

Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428691PMC

The Proteogenomic Landscape of Curable Prostate Cancer.

Cancer Cell 2019 Mar;35(3):414-427.e6

Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Human Genetics, University of California, 12-109 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA; Department of Urology, University of California, Los Angeles, CA 90024, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA 90024, USA; Institute for Precision Health, University of California, Los Angeles, CA 90024, USA. Electronic address:

DNA sequencing has identified recurrent mutations that drive the aggressiveness of prostate cancers. Surprisingly, the influence of genomic, epigenomic, and transcriptomic dysregulation on the tumor proteome remains poorly understood. We profiled the genomes, epigenomes, transcriptomes, and proteomes of 76 localized, intermediate-risk prostate cancers. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.005DOI Listing

Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance.

Cancer Cell 2019 Mar;35(3):347-367

Department of Cancer Biology and David H. Koch Center for Applied Research of Genitourinary Cancers, UT MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address:

Integrins mediate cell adhesion and transmit mechanical and chemical signals to the cell interior. Various mechanisms deregulate integrin signaling in cancer, empowering tumor cells with the ability to proliferate without restraint, to invade through tissue boundaries, and to survive in foreign microenvironments. Recent studies have revealed that integrin signaling drives multiple stem cell functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to oncogene- and immune-targeted therapies. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.007DOI Listing

Capitalizing on Cancer Replication Stress by Preventing PAR Chain Turnover: A New Type of Synthetic Lethality.

Cancer Cell 2019 Mar;35(3):344-346

Molecular Biology Program and Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Tumors resistant to PARP inhibitors frequently show signs of replication stress, with hyper-activated PARP. In this issue of Cancer Cell, Pillay et al. demonstrate that inhibiting PAR-chain turnover results in cell-cycle arrest, which is cytotoxic when combined with cell-cycle checkpoint inhibition and constitutes a novel cancer therapy. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.011DOI Listing

Therapeutic Clues from an Integrated Omic Assessment of East Asian Triple Negative Breast Cancers.

Cancer Cell 2019 Mar;35(3):341-343

Center for Spatial Systems Biomedicine, Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 97201, USA. Electronic address:

In this issue of Cancer Cell, Jiang et al. report a genomic and transcriptional analysis of triple negative breast cancers (TNBCs) from an East Asian population. Their study shows minor differences with published studies of European and North American populations and suggests a therapeutic decision tree for treatment of TNBC. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.012DOI Listing

Serine and Methionine Metabolism: Vulnerabilities in Lethal Prostate Cancer.

Cancer Cell 2019 Mar;35(3):339-341

Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Altered metabolism is a common feature of new and recurring malignancy. In this issue of Cancer Cell, Reina-Campos and colleagues report upregulation of the serine, glycine, one-carbon (SGOC) metabolic network is required for neuroendocrine prostate cancer, a castration-resistant aggressive form of the disease, and presents a targetable vulnerability. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425948PMC

No Matter How You Splice It, RBM39 Inhibition Targets Spliceosome Mutant AML.

Cancer Cell 2019 Mar;35(3):337-339

Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

A report in this issue of Cancer Cell identifies the RNA-binding protein RBM39 as a potential target in spliceosome mutant AML that can be targeted by existing sulfonamide drugs. These results support a proposed clinical trial in patients with myeloid malignancies bearing spliceosome mutations relapsed or refractory to standard therapy. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108193010
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http://dx.doi.org/10.1016/j.ccell.2019.02.013DOI Listing
March 2019
3 Reads

Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies.

Cancer Cell 2019 Mar 7;35(3):428-440.e5. Epub 2019 Mar 7.

Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, P.R. China. Electronic address:

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.02.001DOI Listing
March 2019
3 Reads
23.523 Impact Factor

Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair.

Cancer Cell 2019 Mar 28;35(3):504-518.e7. Epub 2019 Feb 28.

Ludwig Institute for Cancer Research, San Diego Branch, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address:

Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424615PMC
March 2019
23.523 Impact Factor

Hacking the Cancer Genome: Profiling Therapeutically Actionable Long Non-coding RNAs Using CRISPR-Cas9 Screening.

Cancer Cell 2019 Apr 28;35(4):545-557. Epub 2019 Feb 28.

Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland. Electronic address:

Long non-coding RNAs (lncRNAs) represent a huge reservoir of potential cancer targets. Such "onco-lncRNAs" have resisted traditional RNAi methods, but CRISPR-Cas9 genome editing now promises functional screens at high throughput and low cost. The unique biology of lncRNAs demands screening strategies distinct from protein-coding genes. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.019DOI Listing
April 2019
1 Read

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer.

Cancer Cell 2019 Mar 28;35(3):385-400.e9. Epub 2019 Feb 28.

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

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424636PMC
March 2019
1 Read

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia.

Cancer Cell 2019 Mar 21;35(3):369-384.e7. Epub 2019 Feb 21.

Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424627PMC
March 2019
1 Read

ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer.

Cancer Cell 2019 Mar 14;35(3):401-413.e6. Epub 2019 Feb 14.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:

Androgen deprivation therapy for prostate cancer (PCa) benefits patients with early disease, but becomes ineffective as PCa progresses to a castration-resistant state (CRPC). Initially CRPC remains dependent on androgen receptor (AR) signaling, often through increased expression of full-length AR (ARfl) or expression of dominantly active splice variants such as ARv7. We show in ARv7-dependent CRPC models that ARv7 binds together with ARfl to repress transcription of a set of growth-suppressive genes. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.008DOI Listing
March 2019
4 Reads
23.523 Impact Factor

A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK.

Cancer Cell 2019 Mar 14;35(3):457-472.e5. Epub 2019 Feb 14.

Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.009DOI Listing
March 2019
1 Read
23.523 Impact Factor

Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf-Induced Tumorigenesis.

Cancer Cell 2019 Feb;35(2):315-328.e6

CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA. Electronic address:

We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.005DOI Listing
February 2019
4 Reads
23.523 Impact Factor

DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns.

Cancer Cell 2019 Feb;35(2):297-314.e8

Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, 384 Victoria St, Sydney, NSW 2010, Australia; St Vincent's Clinical School, UNSW, Sydney, NSW 2010, Australia. Electronic address:

Promoter CpG islands are typically unmethylated in normal cells, but in cancer a proportion are subject to hypermethylation. Using methylome sequencing we identified CpG islands that display partial methylation encroachment across the 5' or 3' CpG island borders. CpG island methylation encroachment is widespread in prostate and breast cancer and commonly associates with gene suppression. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.004DOI Listing
February 2019
2 Reads
23.523 Impact Factor

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.

Cancer Cell 2019 Feb;35(2):256-266.e5

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Princess Máxima Center for Pediatric Oncology, 3584 CT Utrecht, The Netherlands. Electronic address:

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108183058
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http://dx.doi.org/10.1016/j.ccell.2018.12.011DOI Listing
February 2019
27 Reads

Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy.

Cancer Cell 2019 Feb;35(2):238-255.e6

Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address:

Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.003DOI Listing
February 2019
6 Reads

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells.

Cancer Cell 2019 Feb;35(2):221-237.e8

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108193000
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http://dx.doi.org/10.1016/j.ccell.2019.01.002DOI Listing
February 2019
51 Reads
23.523 Impact Factor

p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors.

Cancer Cell 2019 Feb;35(2):204-220.e9

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address:

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.006DOI Listing
February 2019
7 Reads

UTX Mutations in Human Cancer.

Cancer Cell 2019 Feb;35(2):168-176

Simpson Querrey Center for Epigenetics, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Searle 6-512, 320 E. Superior St., Chicago, IL 60611, USA. Electronic address:

Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine 27 (H3K27). UTX function has been linked to homeotic gene expression, embryonic development, and cellular reprogramming. UTX and its protein interactors within the COMPASS family, including the MLL3 and MLL4 lysine methyltransferases, are frequently mutated in multiple human cancers; however, the molecular basis of how these mutations contribute to oncogenesis remains unclear. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.001DOI Listing
February 2019
1 Read

The Origin of CIMP, At Last.

Cancer Cell 2019 Feb;35(2):165-167

Department of Molecular Biology, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo 060-8556, Japan.

In this issue of Cancer Cell, Tao et al. provide compelling evidence that aging-like DNA methylation of multiple CpG islands, the CpG island methylator phenotype (CIMP), produces a cellular context that can tolerate BRAF activation avoiding senescence by dedicating 5-month culture of colon-derived organoids to epigenomic and stemness analysis. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.015DOI Listing
February 2019
2 Reads

Paradoxical Puma Prohibits Pyruvate Pumps to Prime Pathology.

Authors:
Douglas R Green

Cancer Cell 2019 Feb;35(2):163-165

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

PUMA is a pro-apoptotic Bcl-2 family protein that can act as a tumor suppressor or oncogene in different cancers. In this issue, Kim et al. show that PUMA, independent of its apoptotic function, enforces glycolytic metabolism by inhibiting the transport of pyruvate into the mitochondria, promoting hepatocellular carcinoma. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.016DOI Listing
February 2019
2 Reads

Glutathione Metabolism: An Achilles' Heel of ARID1A-Deficient Tumors.

Cancer Cell 2019 Feb;35(2):161-163

The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, M5G 2M9, Toronto, Canada. Electronic address:

In this issue of Cancer Cell, Ogiwara et al. describe a novel link between the epigenetic regulator ARID1A and glutathione metabolism in cancer that is mediated by regulation of the cystine/glutamate transporter XCT. This work reveals that synthesis of reduced glutathione is a metabolic dependency of cancers with ARID1A-inactivating mutations. Read More

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http://dx.doi.org/10.1016/j.ccell.2019.01.017DOI Listing
February 2019
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A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion.

Cancer Cell 2019 Feb 31;35(2):283-296.e5. Epub 2019 Jan 31.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA, USA. Electronic address:

SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108183058
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http://dx.doi.org/10.1016/j.ccell.2018.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372356PMC
February 2019
9 Reads
23.523 Impact Factor

Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation.

Cancer Cell 2019 Feb 31;35(2):191-203.e8. Epub 2019 Jan 31.

The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China; Cancer Research Institute, Guangdong Provincial Key Laboratory of Cancer Immunotherapy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA. Electronic address:

The tumor suppressor p53 is somatically mutated in half of all human cancers. Paradoxically, the wild-type p53 (WTp53) is often retained in certain human cancers, such as hepatocarcinoma (HCC). We discovered a physiological and oncogenic role of WTp53 in suppressing pyruvate-driven oxidative phosphorylation by inducing PUMA. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.12.012DOI Listing
February 2019
6 Reads
23.523 Impact Factor

Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers.

Cancer Cell 2019 Feb 24;35(2):177-190.e8. Epub 2019 Jan 24.

Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Molecular Oncology, The Jikei University Graduate School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address:

ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.12.009DOI Listing
February 2019
6 Reads