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

L Drusian, EA Nigro, V Mannella, R Pagliarini, M Pema, ASH Costa, F Benigni, A Larcher, M Chiaravalli, E Gaude, F Montorsi, U Capitanio, G Musco, C Frezza, A Boletta

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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. Renal cell carcinomas are common human cancers whose modeling in mice has proved difficult. Drusian et al. show that kidney-specific inactivation of Tsc1 results in benign lesions that gradually transform into malignant carcinomas. Metabolomic profiling revealed that mTORC1 upregulation leads to accumulation of fumarate, an oncometabolite that contributes to transformation. © 2018 The Author(s)
Original languageEnglish
Pages (from-to)1093-1104.e6
JournalCell Reports
Issue number5
Publication statusPublished - 2018


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