Background

Bladder cancer is the tenth most prevalent cancer worldwide. Mutation and inactivation of TSC1 occur in approximately 6-10% of all bladder cancer. TSC1 encodes hamartin and functions as a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1).

Methods

To assess the functional effects of TSC1 loss in bladder cancer, RNA expression data from the TCGA, TSC1-mutant (TSC1_mutBLCA, n=##) was compared with TSC1 wildtype (TSC1_WTBLCA, n=##). Expression differences were confirmed by IHC analysis of five independent TSC1_mutBLCA and TSC1_WTBLCA specimens each, and by in vitro studies using three TSC1_mut and five TSC1_WT BLCA cell lines.

Results

GSEA and DESeq2 identified an increase in lysosomal gene expression in TSC1_mutBLCA, with –, –, –, –, and – genes showing the greatest increase in TCGA. Notably, TFE3, regulator of lysosomal gene expression, was elevated in expression and localized to the nucleus in TSC1_mutBLCA by IHC on local BLCA cases. Nuclear localization of TFE3 was seen in TSC1_mutBLCA cell lines, and partially reversed by rapamycin (mTOR inhibitor) treatment, leading to reduced expression of lysosomal genes.

Conclusions

Our findings indicate that TSC1 mutant bladder tumors are characterized by activation of TFE3, which likely contributes to TSC1_mutBLCA development, and is a potential therapeutic target.