mTORC1 Upregulation Leads to Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma.

Renal cell carcinomas (RCCs) are common cancers diagnosed in more than 350,000 people each year worldwide. Several pathways are de-regulated in RCCs, including mTORC1. However, how mTOR drives tumorigenesis in this context is unknown. The lack of faithful animal models has limited progress in understanding and targeting RCCs. Here, we generated a mouse model harboring the kidney-specific inactivation of Tsc1. These animals develop cysts that evolve into papillae, cystadenomas, and papillary carcinomas. Global profiling confirmed several metabolic derangements previously attributed to mTORC1. Notably, Tsc1 inactivation results in the accumulation of fumarate and in mTOR-dependent downregulation of the TCA cycle enzyme fumarate hydratase (FH). The re-expression of FH in cellular systems lacking Tsc1 partially rescued renal epithelial transformation. Importantly, the mTORC1-FH axis is likely conserved in human RCC specimens. We reveal a role of mTORC1 in renal tumorigenesis, which depends on the oncometabolite fumarate.

Cell reports. 2018 Jul 31 [Epub]

Luca Drusian, Elisa Agnese Nigro, Valeria Mannella, Roberto Pagliarini, Monika Pema, Ana S H Costa, Fabio Benigni, Alessandro Larcher, Marco Chiaravalli, Edoardo Gaude, Francesco Montorsi, Umberto Capitanio, Giovanna Musco, Christian Frezza, Alessandra Boletta

Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy; PhD Program in Biology and Biotherapy of Cancer, Università Vita-Salute San Raffaele, Milan, Italy., Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Biomolecular NMR Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy., MRC, Cancer Unit Cambridge, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK., Urological Research Institute (URI), IRCCS San Raffaele Scientific Institute, Milan, Italy., Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Urological Research Institute (URI), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: .

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