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).
To assess the functional effects of TSC1 loss in bladder cancer, RNA expression data from the TCGA, TSC1-mutant (TSC1mutBLCA, n=##) was compared with TSC1 wildtype (TSC1WTBLCA, n=##). Expression differences were confirmed by IHC analysis of five independent TSC1mutBLCA and TSC1WTBLCA specimens each, and by in vitro studies using three TSC1mut and five TSC1WT BLCA cell lines.
GSEA and DESeq2 identified an increase in lysosomal gene expression in TSC1mutBLCA, 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 TSC1mutBLCA by IHC on local BLCA cases. Nuclear localization of TFE3 was seen in TSC1mutBLCA cell lines, and partially reversed by rapamycin (mTOR inhibitor) treatment, leading to reduced expression of lysosomal genes.
Our findings indicate that TSC1 mutant bladder tumors are characterized by activation of TFE3, which likely contributes to TSC1mutBLCA development, and is a potential therapeutic target.