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      NSD2 is a conserved driver of metastatic prostate cancer progression

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          Abstract

          Deciphering cell-intrinsic mechanisms of metastasis progression in vivo is essential to identify novel therapeutic approaches. Here we elucidate cell-intrinsic drivers of metastatic prostate cancer progression through analyses of genetically engineered mouse models (GEMM) and correlative studies of human prostate cancer. Expression profiling of lineage-marked cells from mouse primary tumors and metastases defines a signature of de novo metastatic progression. Cross-species master regulator analyses comparing this mouse signature with a comparable human signature identifies conserved drivers of metastatic progression with demonstrable clinical and functional relevance. In particular, nuclear receptor binding SET Domain Protein 2 ( NSD2) is robustly expressed in lethal prostate cancer in humans, while its silencing inhibits metastasis of mouse allografts in vivo. We propose that cross-species analysis can elucidate mechanisms of metastasis progression, thus providing potential additional therapeutic opportunities for treatment of lethal prostate cancer.

          Abstract

          Identifying cell intrinsic mechanisms promoting metastasis are necessary to develop new cancer therapeutics. Here they do cross-species computational analysis and identify nuclear receptor binding SET domain Protein 2 (NSD2) as a driver of prostate cancer metastasis.

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          Cancer Statistics, 2017.

          Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2017)
          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017;67:7-30. © 2017 American Cancer Society.
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            Emerging Biological Principles of Metastasis.

            Arthur Lambert, Diwakar Pattabiraman, Robert Weinberg (2017)
            Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of research concerning metastasis continues to grow at a rapid rate, the biological programs that underlie the dissemination and metastatic outgrowth of cancer cells are beginning to come into view. In this review we summarize the cellular and molecular mechanisms involved in metastasis, with a focus on carcinomas where the most is known, and we highlight the general principles of metastasis that have begun to emerge.
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              Integrative clinical genomics of advanced prostate cancer.

              Dan Robinson, Eliezer M. Van Allen, Yi-Mi Wu … (2015)
              Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals. Copyright © 2015 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Alvaro Aytes: aaytes@idibell.cat
                Andrea Califano: ac2248@cumc.columbia.edu
                Cory Abate-Shen: cabateshen@columbia.edu
                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 5 December 2018
                Publication date PMC-release: 5 December 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 5201
                Affiliations
                [1 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Urology, , Columbia University Irving Medical Center, ; 160 Fort Washington Ave, New York, NY 10032 USA
                [2 ]Programs of Molecular Mechanisms and Experimental Therapeutics in Oncology (ONCOBell), and Cancer Therapeutics Resistance (ProCURE), Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Gran Via de L’Hospitalet, 199, 08908 Barcelona, Spain
                [3 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Medicine, , Columbia University Irving Medical Center, ; 630W 168th Street, New York, NY 10032 USA
                [4 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Systems Biology, , Columbia University Irving Medical Center, ; 1130 Saint Nicholas Ave, New York, NY 10032 USA
                [5 ]ISNI 0000 0004 1936 8796, GRID grid.430387.b, Department of Health Informatics, Rutgers School of Health Professions, Rutgers, , The State University of New Jersey, ; 65 Bergen Street, Newark, NJ 07101 USA
                [6 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Pathology and Laboratory Medicine, , Weill Cornell Medicine, ; 1300 York Avenue, New York, NY 10065 USA
                [7 ]ISNI 0000 0001 0726 5157, GRID grid.5734.5, Department for BioMedical Research, , University of Bern, ; Murtenstrasse 35, CH-3008 Bern, Switzerland
                [8 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Genetics and Development, , Columbia University Irving Medical Center, ; 701 West 168th Street, New York, NY 10032 USA
                [9 ]ISNI 0000000419368729, GRID grid.21729.3f, Herbert Irving Comprehensive Cancer Center, , Columbia University Irving Medical Center, ; 1130 Saint Nicholas Ave, New York, NY 10032 USA
                [10 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Biochemistry and Molecular Biophysics, , Columbia University Irving Medical Center, ; 701 West 168th Street, New York, NY 10032 USA
                [11 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Pathology and Cell Biology, , Columbia University Irving Medical Center, ; 630W 168th Street, New York, NY 10032 USA
                Author information
                http://orcid.org/0000-0002-4042-1657
                Article
                Publisher ID: 7511
                DOI: 10.1038/s41467-018-07511-4
                PMC ID: 6281610
                PubMed ID: 30518758
                SO-VID: aeef1536-f669-43a7-af9b-8256c2af7c55
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 3 February 2018
                Date accepted : 6 November 2018
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                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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