2,656 results match your criteria Cancer Cell [Journal]


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
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
1 Read

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
3 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

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
7 Reads

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
1 Read

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

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

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
1 Read

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
1 Read

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
1 Read
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

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

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases.

Cancer Cell 2019 Feb 24;35(2):267-282.e7. Epub 2019 Jan 24.

PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON M5G 2M9, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. Electronic address:

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. 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.2018.12.010DOI Listing
February 2019
1 Read

Tails of a Super Histone.

Cancer Cell 2019 Jan;35(1):7-9

Arthur and Sonia Labatt Brain Tumour Research Centre, Department of Pediatrics/Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5S3H7, Canada; Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S3H7, Canada. Electronic address:

Diffuse intrinsic brain stem gliomas (DIPGs) with characteristic K27M mutation of H3.3 are lethal and poorly understood childhood cancers. In this issue of Cancer Cell, Larson et al. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.12.005DOI Listing
January 2019
1 Read

The Deadly Bite of STAT3.

Cancer Cell 2019 Jan;35(1):5-7

Division of Infection and Immunity, University College London, London WC1E 4JF, UK. Electronic address:

The Tasmanian devils' facial tumor disease (DFTD) is a transmissible cancer that spreads by biting and threatens extinction of this marsupial. In this issue of Cancer Cell, Kosack et al. describe how overexpression of ERBB and uncontrolled activation of STAT3 drive DFTD growth and immune evasion. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108183057
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http://dx.doi.org/10.1016/j.ccell.2018.12.004DOI Listing
January 2019
4 Reads

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.

Cancer Cell 2019 Jan;35(1):33-45.e6

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108183055
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http://dx.doi.org/10.1016/j.ccell.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336114PMC
January 2019
7 Reads

Tumor Extracellular Vesicles Impede Interferon Alert Responses.

Cancer Cell 2019 Jan;35(1):3-5

Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Tumor-derived extracellular vesicles promote metastasis by inducing functional changes in cells at pre-metastatic sites conducive for tumor cell colonization. In this issue of Cancer Cell, Ortiz and colleagues show that type I interferon regulates extracellular vesicle uptake and that modulating this pathway holds promise for treating metastasis. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.12.006DOI Listing
January 2019
5 Reads

Gain Fat-Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis.

Cancer Cell 2019 Jan;35(1):17-32.e6

Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Electronic address:

Cancer cell plasticity facilitates the development of therapy resistance and malignant progression. De-differentiation processes, such as an epithelial-mesenchymal transition (EMT), are known to enhance cellular plasticity. Here, we demonstrate that cancer cell plasticity can be exploited therapeutically by forcing the trans-differentiation of EMT-derived breast cancer cells into post-mitotic and functional adipocytes. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.12.002DOI Listing
January 2019
30 Reads

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

Cancer Cell 2019 Jan;35(1):125-139.e9

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address:

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335503PMC
January 2019
7 Reads

Proteogenomic Characterization of Human Early-Onset Gastric Cancer.

Cancer Cell 2019 Jan;35(1):111-124.e10

Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu 711-873, Republic of Korea. Electronic address:

We report proteogenomic analysis of diffuse gastric cancers (GCs) in young populations. Phosphoproteome data elucidated signaling pathways associated with somatic mutations based on mutation-phosphorylation correlations. Moreover, correlations between mRNA and protein abundances provided potential oncogenes and tumor suppressors associated with patient survival. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108183057
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http://dx.doi.org/10.1016/j.ccell.2018.12.003DOI Listing
January 2019
19 Reads
23.523 Impact Factor

The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters.

Cancer Cell 2019 Jan;35(1):10-15

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

We propose that initiating truncal mutations plays a special role in tumor formation by both enhancing the survival of the initiating cancer cell and by selecting for secondary mutations that contribute to tumor progression, and that these mutations often act in a tissue-preferred fashion. Here, we explain why inherited mutations often have different tissue specificities compared with spontaneous mutations in the same gene. Initiating truncal mutations make excellent neo-antigens for immunotherapy, and understanding why one mutation selects for a second mutation in a particular tissue type could one day aid in the design of gene-targeted combination therapies. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376970PMC
January 2019
1 Read

Hijacking EMT: Better Fat Than Dead.

Cancer Cell 2019 Jan;35(1):1-2

Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA. Electronic address:

Potential for cancers to form metastases requires cell dissemination utilizing epithelial-to-mesenchymal transition (EMT) program. In this issue of Cancer Cell, Ishay-Ronen et al. show that plasticity intrinsic to the EMT program can be exploited to divert cancer cells into becoming post-mitotic adipocytes, thus preventing formation of metastases. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.12.007DOI Listing
January 2019
1 Read

Tinagl1 Suppresses Triple-Negative Breast Cancer Progression and Metastasis by Simultaneously Inhibiting Integrin/FAK and EGFR Signaling.

Cancer Cell 2019 Jan 3;35(1):64-80.e7. Epub 2019 Jan 3.

Department of Molecular Biology, Princeton University, Washington Road, LTL 255, Princeton, NJ 08544, USA; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA. Electronic address:

Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5β1, αvβ1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.016DOI Listing
January 2019
1 Read
23.523 Impact Factor

Hyper-Editing of Cell-Cycle Regulatory and Tumor Suppressor RNA Promotes Malignant Progenitor Propagation.

Cancer Cell 2019 Jan 3;35(1):81-94.e7. Epub 2019 Jan 3.

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; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address:

Adenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333511PMC
January 2019
2 Reads
23.523 Impact Factor

Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression.

Cancer Cell 2019 Jan 27;35(1):140-155.e7. Epub 2018 Dec 27.

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

Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brainstem tumors with frequent histone H3 K27M mutations and recurrent alterations in PDGFRA and TP53. We generated genetically engineered inducible mice and showed that H3.3 K27M enhanced neural stem cell self-renewal while preserving regional identity. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.015DOI Listing
January 2019
2 Reads

Comprehensive Analysis of Chromatin States in Atypical Teratoid/Rhabdoid Tumor Identifies Diverging Roles for SWI/SNF and Polycomb in Gene Regulation.

Cancer Cell 2019 Jan 27;35(1):95-110.e8. Epub 2018 Dec 27.

Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108183053
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http://dx.doi.org/10.1016/j.ccell.2018.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341227PMC
January 2019
4 Reads

p62/SQSTM1 Fuels Melanoma Progression by Opposing mRNA Decay of a Selective Set of Pro-metastatic Factors.

Cancer Cell 2019 Jan 20;35(1):46-63.e10. Epub 2018 Dec 20.

Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain. Electronic address:

Modulators of mRNA stability are not well understood in melanoma, an aggressive tumor with complex changes in the transcriptome. Here we report the ability of p62/SQSTM1 to extend mRNA half-life of a spectrum of pro-metastatic factors. These include FERMT2 and other transcripts with no previous links to melanoma. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.008DOI Listing
January 2019
2 Reads
23.523 Impact Factor

Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.

Cancer Cell 2018 Dec;34(6):996-1011.e8

Finsen Laboratory, Rigshospitalet, DK-2200, Copenhagen, Denmark; Biotech Research & Innovation Centre (BRIC), University of Copenhagen, DK-2200, Copenhagen, Denmark; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69120 Heidelberg, Germany; Charité Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. Electronic address:

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.10.016DOI Listing
December 2018
14 Reads
23.523 Impact Factor

Targeting PKCδ as a Therapeutic Strategy against Heterogeneous Mechanisms of EGFR Inhibitor Resistance in EGFR-Mutant Lung Cancer.

Cancer Cell 2018 Dec;34(6):954-969.e4

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address:

Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.007DOI Listing
December 2018
7 Reads
23.523 Impact Factor

Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling.

Cancer Cell 2018 Dec;34(6):922-938.e7

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352909PMC
December 2018
7 Reads
23.523 Impact Factor

Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia.

Cancer Cell 2018 Dec;34(6):906-921.e8

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia. Electronic address:

Glucocorticoids play a critical role in the treatment of lymphoid malignancies. While glucocorticoid efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. Here, we studied genome-wide lymphocyte-specific open chromatin domains (LSOs), and integrated LSOs with glucocorticoid-induced RNA transcription and chromatin modulation using an in vivo patient-derived xenograft model of acute lymphoblastic leukemia (ALL). Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.002DOI Listing
December 2018
2 Reads
23.523 Impact Factor

Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway.

Cancer Cell 2018 Dec;34(6):893-905.e8

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; Breast Medicine Service, Department of Medicine, MSKCC, New York, NY 10065, USA; Weill-Cornell Medical College, New York, NY 10065, USA. Electronic address:

Cyclin dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) are effective in breast cancer; however, drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of 348 estrogen receptor-positive (ER) breast cancers treated with CDK4/6i and identified loss-of-function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6, the suppression of which restored sensitivity to CDK4/6i. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294301PMC
December 2018
22 Reads

BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines.

Cancer Cell 2018 Dec;34(6):879-891

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:

Defects in apoptotic cell death can promote cancer and impair responses of malignant cells to anti-cancer therapy. Pro-survival BCL-2 proteins prevent apoptosis by keeping the cell death effectors, BAX and BAK, in check. The BH3-only proteins initiate apoptosis by neutralizing the pro-survival BCL-2 proteins. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.004DOI Listing
December 2018
16 Reads

Immunodivergence in Metastatic Colorectal Cancer.

Cancer Cell 2018 Dec;34(6):876-878

Clinica Universidad de Navarra, Pamplona, Spain; CIBERONC, Madrid, Spain; Center for applied Medical Research (CIMA), Pamplona, Spain; IDISNA, Pamplona, Spain. Electronic address:

Van den Eynde et al. publish in this issue of Cancer Cell that metastatic colorectal cancer shows marked heterogeneity in T cell infiltration among different lesions and patients. Measurements of T cell infiltration in metastases by immunoscore offer some prognostic information and support immune editing by coevolving adaptive immune responses. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.012DOI Listing
December 2018
3 Reads

Initiation and Evolution of Early Onset Prostate Cancer.

Cancer Cell 2018 Dec;34(6):874-876

Hematology-Oncology Division, Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

In this issue of Cancer Cell, Gerhauser et al. analyze early-onset prostate cancers, showing roles for androgen receptor-driven rearrangements, an early APOBEC-driven mutational mechanism, and ESRP1 gene duplication. Through integration of whole-genome, transcriptome, and methylome data, they identify high-risk subgroups and develop an algorithm that may predict molecular evolution. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.010DOI Listing
December 2018
8 Reads

From Basic Knowledge to Effective Therapies.

Cancer Cell 2018 Dec;34(6):871-873

Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany; The German Cancer Research Consortium. Electronic address:

In this issue of Cancer Cell, Ott et al. use integrative analysis of histone ChIP-seq and ATAC-seq to describe enhancer-based regulatory circuits in chronic lymphocytic leukemia. This work identified and validated transcription factor PAX5 as main driver of an oncogenic circuitry, which can be disrupted by BET bromodomain inhibition. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.013DOI Listing
December 2018
2 Reads

Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally.

Cancer Cell 2018 Dec;34(6):869-871

Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA. Electronic address:

Glucocorticoid resistance represents a major challenge in treating acute lymphoblastic leukemia. In this issue of Cancer Cell, Jing and colleagues show epigenetic deregulation of glucocorticoid-induced BIM activation in glucocorticoid-resistant leukemia cells, and restore glucocorticoid-receptor-induced BIM upregulation with DNA demethylating agents to effectively enhance glucocorticoid response. Read More

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December 2018
2 Reads

The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients.

Cancer Cell 2018 Dec;34(6):1012-1026.e3

INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address:

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.003DOI Listing
December 2018
15 Reads
23.523 Impact Factor

A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence.

Cancer Cell 2018 Dec 29;34(6):970-981.e8. Epub 2018 Nov 29.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

The Mixed Lineage Leukemia gene (MLL) is altered in leukemia by chromosomal translocations to produce oncoproteins composed of the MLL N-terminus fused to the C-terminus of a partner protein. Here, we used domain-focused CRISPR screening to identify ZFP64 as an essential transcription factor in MLL-rearranged leukemia. We show that the critical function of ZFP64 in leukemia is to maintain MLL expression via binding to the MLL promoter, which is the most enriched location of ZFP64 occupancy in the human genome. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.10.015DOI Listing
December 2018
2 Reads

Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia.

Cancer Cell 2018 Dec 29;34(6):982-995.e7. Epub 2018 Nov 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address:

Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298230PMC
December 2018
16 Reads

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance.

Cancer Cell 2018 Dec 21;34(6):939-953.e9. Epub 2018 Nov 21.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA. Electronic address:

Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER breast tumors. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310147PMC
December 2018
9 Reads

Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations.

Cancer Cell 2018 Nov 25;34(5):792-806.e5. Epub 2018 Oct 25.

Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address:

Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent mutations in HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) that include G660D, R678Q, E693K, and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S15356108183042
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http://dx.doi.org/10.1016/j.ccell.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248889PMC
November 2018
22 Reads
23.523 Impact Factor

The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability.

Cancer Cell 2018 Nov;34(5):823-839.e7

Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, BCM600, One Baylor Plaza, Houston, TX 77030, USA. Electronic address:

The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. Read More

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http://dx.doi.org/10.1016/j.ccell.2018.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239211PMC
November 2018
3 Reads
23.523 Impact Factor