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

Abstract

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.

Liver neoplasms in methylmalonic aciduria: An emerging complication

“…So far, three oncometabolites have been identified in organic acidurias: fumarate (fumarate hydratase deficiency), succinate (succinate dehydrogenase deficiency) and D‐2‐hydroxyglutarate (D‐2‐hydroxyglutaric aciduria type I and II). While evidence of oncometabolites in MMA is lacking, renal cell carcinoma kidneys of an MMA patient were found to carry a somatic knock‐out mutation for the TSC1 gene encoding hamartin, shown to cause accumulation of fumarate . Hence, further genomic investigations of case 2 might help to understand their presentation of a multicystic dysplastic kidney.…”

“…While evidence of oncometabolites in MMA is lacking, renal cell carcinoma kidneys of an MMA patient were found to carry a somatic knock-out mutation for the TSC1 gene encoding hamartin, 29 shown to cause accumulation of fumarate. 30 Hence, further genomic investigations of case 2 might help to understand their presentation of a multicystic dysplastic kidney. In addition, environmental factors such as exposure to exogenous hepatotoxic compounds or oncogenic viruses are parameters that need to be carefully taken into consideration in discussing the causative pathophysiological mechanisms of liver oncogenicity.…”

mTORC1-driven accumulation of the oncometabolite fumarate as a potential critical step in renal cancer progression

“…In a recent study, we described a novel animal model faithfully and robustly recapitulating a papillary type II Renal Cell Carcinoma (PRCC). 1 Of interest, this was obtained by inactivation of a single tumor suppressor gene, Tuberous Sclerosis Complex 1 Tsc1, a master negative regulator of the mTORC1 complex. We found that inactivation of the Tsc1 gene in a renal tubular segment-restricted Cre mouse line (Cadherin 16-Cre, also called Kidney Specific Cre, Ksp-Cre) results in a mild renal cystogenesis.…”

“…1 Importantly, the different type of lesions are progressive and occur with full-penetrance at different time points after birth of the animals. 1 Mechanistic studies on these tissues revealed an unexpected and previously unsuspected link between two important tumorigenic cascades in the kidney: that of the mTORC1 3 and the tumor suppressor Fumarate Hydratase (FH) whose impairment leads to accumulation of the oncometabolite fumarate. 4 There are several relevant novel aspects related to the above study.…”

“…9 One important feature of the animal model described is the progressive transformation from benign, cystic lesions, to the formation of cystadenomas and carcinomas. 1 This important feature allowed for the dissection of metabolic alterations in the pre-malignant versus malignant lesions. Indeed, untargeted metabolomics revealed metabolic changes in the cancerous versus precancerous mutant kidneys, some of which were expected based on previous work in non-renal cancers, such as glycolysis, pentose phosphate pathway, purine biosynthesis and fatty acids biosynthesis.…”