Journal article
Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade
Cancer discovery, Vol.7(8), pp.900-917
08/2017
DOI: 10.1158/2159-8290.CD-17-0292
PMCID: PMC5540776
PMID: 28473526
Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by and mutations, which are associated with tumors of different grade and prognosis. However, whether and loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted and (with ) in the mouse using several Cre drivers. and proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. -deficient tumors were of high grade and showed greater mTORC1 activation than -deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, , in -deficient kidneys triggered higher grade ccRCC. This study establishes and as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells. Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that and loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. .
Details
- Title: Subtitle
- Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade
- Creators
- Yi-Feng Gu - Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TexasShannon Cohn - Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TexasAlana Christie - Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TexasTiffani McKenzie - Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TexasNicholas Wolff - Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TexasQuyen N Do - Department of Radiology and the Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TexasAnanth J Madhuranthakam - Department of Radiology and the Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TexasIvan Pedrosa - Department of Radiology and the Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TexasTao Wang - Quantitative Biomedical Research Center, Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, TexasAnwesha Dey - Department of Molecular Oncology, Genentech, South San Francisco, CaliforniaMeinrad Busslinger - The Research Institute of Molecular Pathology, Vienna, AustriaXian-Jin Xie - Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, TexasRobert E Hammer - Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TexasRenée M McKay - Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TexasPayal Kapur - Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TexasJames Brugarolas - Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
- Resource Type
- Journal article
- Publication Details
- Cancer discovery, Vol.7(8), pp.900-917
- Publisher
- United States
- DOI
- 10.1158/2159-8290.CD-17-0292
- PMID
- 28473526
- PMCID
- PMC5540776
- ISSN
- 2159-8290
- eISSN
- 2159-8290
- Grant note
- P30 CA142543 / NCI NIH HHS R01 CA154475 / NCI NIH HHS R01 CA175754 / NCI NIH HHS R03 ES026397 / NIEHS NIH HHS P50 CA196516 / NCI NIH HHS
- Language
- English
- Date published
- 08/2017
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917669402771
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