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      Modeling Renal Cell Carcinoma in mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

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          Abstract

          Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutation, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with Pax8, a developmental lineage-specific transcription factor, led to ccRCC of different grade. Bap1-deficient tumors were high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histological grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCC may arise from Bowman capsule cells.

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          Author and article information

          Journal
          101561693
          39259
          Cancer Discov
          Cancer Discov
          Cancer discovery
          2159-8274
          2159-8290
          16 May 2017
          04 May 2017
          August 2017
          01 August 2018
          : 7
          : 8
          : 900-917
          Affiliations
          [1 ]Department of Internal Medicine, Hematology-Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas
          [2 ]Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
          [3 ]Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
          [4 ]Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
          [5 ]Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
          [6 ]Department of Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California
          [7 ]The Research Institute of Molecular Pathology, Vienna, Austria
          [8 ]Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
          [9 ]Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
          Author notes
          Corresponding Author: James Brugarolas, University of Texas Southwestern Medical Center. 5323 Harry Hines Blvd., Dallas, TX, USA, 75390-8852. Phone: 214-648-4059; Fax: 214-648-1955. james.brugarolas@ 123456utsouthwestern.edu
          Corresponding Author: Payal Kapur, University of Texas Southwestern Medical Center. 5323 Harry Hines Blvd., Dallas, TX, USA, 75390-8852. Phone: 214-633-6363; Fax: 214-648-4067. payal.kapur@ 123456utsouthwestern.edu
          Article
          PMC5540776 PMC5540776 5540776 nihpa874898
          10.1158/2159-8290.CD-17-0292
          5540776
          28473526
          5a8744f8-14ec-4d81-b389-602d8e836d58
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