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      Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway.

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          Abstract

          Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          J. Gao, B. A. Aksoy, U Dogrusoz … (2015)
          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            Identification of multipotent luminal progenitor cells in human prostate organoid cultures.

            Wouter Karthaus, Phillip J. Iaquinta, Jarno Drost … (2014)
            The prostate gland consists of basal and luminal cells arranged as pseudostratified epithelium. In tissue recombination models, only basal cells reconstitute a complete prostate gland, yet murine lineage-tracing experiments show that luminal cells generate basal cells. It has remained challenging to address the molecular details of these transitions and whether they apply to humans, due to the lack of culture conditions that recapitulate prostate gland architecture. Here, we describe a 3D culture system that supports long-term expansion of primary mouse and human prostate organoids, composed of fully differentiated CK5+ basal and CK8+ luminal cells. Organoids are genetically stable, reconstitute prostate glands in recombination assays, and can be experimentally manipulated. Single human luminal and basal cells give rise to organoids, yet luminal-cell-derived organoids more closely resemble prostate glands. These data support a luminal multilineage progenitor cell model for prostate tissue and establish a robust, scalable system for mechanistic studies. Copyright © 2014 Elsevier Inc. All rights reserved.
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              CRISPR-mediated direct mutation of cancer genes in the mouse liver

              Wen-Bin Xue, Sidi Chen, Hao Yin … (2014)
              The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem (ES) cells 1 . Here we describe a new method of cancer model generation using the CRISPR/Cas system in vivo in wild-type mice. We have used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs) 2–4 to the liver and directly target the tumor suppressor genes Pten 5 and p53 6 , alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology 7, 8 . Simultaneous targeting of Pten and p53 induced liver tumors that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumor tissue revealed insertion or deletion (indel) mutations of the tumor suppressor genes, including bi-allelic mutations of both Pten and p53 in tumors. Furthermore, co-injection of Cas9 plasmids harboring sgRNAs targeting the β-Catenin gene (Ctnnb1) and a single-stranded DNA (ssDNA) oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of β-Catenin. This study demonstrates the feasibility of direct mutation of tumor suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Science
                Title: Science (New York, N.Y.)
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Electronic): 1095-9203
                ISSN (Print): 0036-8075
                Publication date (Electronic): May 17 2019
                Volume: 364
                Issue: 6441
                Affiliations
                [1 ] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
                [2 ] Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
                [3 ] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
                [4 ] Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
                [5 ] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
                [6 ] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
                [7 ] Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
                [8 ] Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
                [9 ] Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
                [10 ] Department of Molecular Biotechnology and Health Sciences, and GenoBiToUS, Genomics and Bioinformatics Service, University of Turin, Turin, Italy.
                [11 ] Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
                [12 ] Department of Public Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
                [13 ] Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.
                [14 ] Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
                [15 ] Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
                [16 ] Intonation Research Laboratories, Hyderabad, India.
                [17 ] Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
                [18 ] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA. ppandolf@bidmc.harvard.edu.
                Article
                Publisher Item ID: 364/6441/eaau0159 Mid ID: NIHMS1562813
                DOI: 10.1126/science.aau0159
                PMC ID: 7081834
                PubMed ID: 31097636
                SO-VID: b5c5500b-fdb7-44f0-9b56-4a3db50ec7c6
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