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

Cell Rep. 2018 Jul 31;24(5):1093-1104.e6. doi: 10.1016/j.celrep.2018.06.106.


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.

Keywords: TCA cycle; cancer metabolism; cancer signaling; epithelial transformation; fumarate hydratase; metabolic reprogramming; papillary carcinoma; rapamycin; renal cancer; renal cysts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cells, Cultured
  • Female
  • Fumarate Hydratase / genetics
  • Fumarate Hydratase / metabolism
  • Fumarates / metabolism*
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Tuberous Sclerosis Complex 1 Protein / genetics*
  • Up-Regulation


  • Fumarates
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Mechanistic Target of Rapamycin Complex 1
  • Fumarate Hydratase