Dissecting the Metabolic Rewiring Mediated by SMARCB1 Loss in Metastatic Bladder Cancer

About This Grant

Project Summary Bladder cancer (BLCA), the sixth most common cancer in the United States and 9th overall among all cancers, is rarely diagnosed in individuals aged <40 years. The Cancer Genome Atlas (TCGA) described the genomic landscape of BLCA patients and noted that >60% of cases have alterations in subunits of SWItch/sucrose non- fermentable (SWI/SNF) nucleosome remodeling complexes, such as SMARCB1, also known as integrase interactor 1 (INI-1). Presently, the response rate of BLCA to standard-of-care therapies is relatively low, and therefore, the identification of novel metabolic pathway-mediated druggable targets is urgently needed. Our preliminary data demonstrate that SMARCB1 loss expression has a significantly worse prognosis in patients with BLCA. Orthotopically implanted SMARCB1-knockout (KO) xenograft shows enhanced tumor growth and metastasis. While attempting to identify the metabolic landscape mediated by SMARCB1 loss BLCA, we have identified altered methionine metabolism, nucleotide synthesis, and glutathione metabolism. Our current proposal will seek to define further the metabolic pathway by SMARCB1 loss in BLCA progression as well as immunometabolism and determine whether the key pathways can be therapeutically targeted for the treatment of BLCA. In aim 1, Determine the metabolic alteration by SMARCB1-loss BLCA tumor cells and tumor infiltrating immune cells. In aim 2, Trace the key metabolic pathways in SMARCB1 loss metastatic BLCA. At the level of basic biology, this project aims to understand the metabolic rewiring mediated by SMARCB1 loss in BLCA progression as well as immunometabolism and metastasis by utilizing cutting-edge high-resolution mass spectrometry techniques to profile the metastatic mediated tumors cells and immunometabolism harboring SMARCB1 loss. This will further examine the pathway-specific metabolic regulation non-invasive liquid diet delivery of stable isotopes into mouse models, which will lay the foundation to test the therapeutic strategy in the future.