Clemens Probst, MS

Graduate Student
Genetics, Medical Oncology, Pulmonary and Critical Care Medicine, Urology
TSC1 mutant bladder cancer has a distinct phenotype characterized by lysosomal gene expression and nuclear localization of TFE3

Principal Investigator: David J. Kwiatkowski

Authors: Clemens K. Probst Elio Adib, Heng Du, Michelle S. Hirsch, Krinio Giannikou
Lay Abstract

Bladder cancer is the sixth most common cancer in the United States. Each year, more than 80,000 Americans are newly diagnosed and approximately 18,000 are estimated to die from their disease. Modern treatment options aim to identify the genetic drivers of the disease, enabling personalized and targeted therapy. TSC1 mutations occur in approximately 10-15% of all bladder cancers, but whether they function as drivers of cancer development is unknown. To answer this question, we set out to investigate the downstream pathways of TSC1 mutant bladder cancer and compared them to other cancers in which TSC1 mutation status was driving tumor development. This strategy allowed us to identify a new pathway downstream of TSC1 loss, namely the activation of the transcription factor TFE3, which functions as a master regulator of stress responses inside cells. Our findings expand on the current understanding of TSC1 loss in bladder and we are hopeful that further characterization of this pathway will lead to new and effective treatment options for patients with TSC1 mutant bladder cancer.

Scientific Abstract

Background: Mutations in the tumor suppressor TSC1 gene is a frequent event in bladder cancer (BLCA), however whether it functions as a driver for tumor development is uncertain.

Aim: To investigate the functional role of TSC1 loss in BLCA and to identify novel downstream pathways that are of therapeutic value.

Methods: We performed differential gene expression and pathway analyses using RNA-seq data from the curated TCGA TSC1 mutant BLCA (n=26) and TSC1 wild-type BLCA (n=382) cohort and compared to an internal cohort of putative TSC1/TSC2-driven tumors (n=63). RNA-seq and H3K27ac ChIP-seq were conducted in 3 TSC1 mutant/WT BLCA cell lines.

Results: Integrative analyses, using DESeq2 and GSEA data, revealed a conserved TSC-associated signature, which implicated mTORC1 hyperactivation, as well as abnormal lysosomal processes as a direct consequence of TSC1 inactivation in BLCA. We validated our findings by immunohistochemistry in TSC1-mutant (n=5) and TSC1 WT (n=5) BLCA tissues and found that activation of lysosomal processes was likely driven by nuclear localization of TFE3. Mechanistic studies showed increased post- translational modification of TFE3 in TSC1-null cells, likely driving activation and subsequent induction of lysosomal gene expression.

Conclusions: TSC1-BLCA comprises a distinct subtype of bladder cancer which retains elements of a conserved transcriptional program.

Clinical Implications
Our findings are of clinical relevance because they expand our current understanding of TSC1 loss in bladder cancer beyond mTORC1 overactivation and thus may help to uncover new therapeutic strategies for patients with TSC1 mutations.

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