Abstract 2417: Elucidating the role of SMARCB1 in bladder cancer progression and metastasis

Abstract

Abstract Bladder cancer (BLCA) is the second most common urological malignancy in the US and is usually not curable at an advanced stage. The transcriptomic profiling data of bladder cancer revealed that 64% of BLCA patients have frequent dysregulation of the components of the SWI/SNF, a chromatin remodeling complex. Alterations in chromatin remodeling genes have been previously implicated in human oncogenesis. SMARCB1/INI1 is one of the critical core components of the SWI/SNF complex. In this study, we demonstrate that primary BLCA patients harboring SMARCB1 loss strongly associate with worse survival. Specifically, the biallelic inactivation of the SMARCB1 (SMARCB1 knockout (KO)) in BLCA cell lines resulted in the emergence of aggressive tumor growth leading to soft tissue metastasis to lungs, liver, kidney, and intestine in vivo. Mechanistic studies revealed that IL-6- STAT3 axis is upregulated in SMARCB1 KO BLCA cells. Our data suggest that the STAT3 specific inhibitor, inhibits invasive potential of SMARCB1 KO cells suggesting potential therapeutic efficacy for STAT3 inhibitor to treat subsets of BLCA harboring SMARCB1 loss. In addition, we identified a unique transcriptional signature activated upon SMARCB1 loss, which is predictive of poor patient outcome in BLCA, and hence may be clinically valuable. Bladder cancer (BLCA) is the second most common urological malignancy in the US and is usually not curable at an advanced stage. The transcriptomic profiling data of bladder cancer revealed that 64% of BLCA patients have frequent dysregulation of the components of the SWI/SNF, a chromatin remodeling complex. Alterations in chromatin remodeling genes have been previously implicated in human oncogenesis. SMARCB1/INI1 is one of the critical core components of the SWI/SNF complex. In this study, we demonstrate that primary BLCA patients harboring SMARCB1 loss strongly associate with worse survival. Specifically, the biallelic inactivation of the SMARCB1 (SMARCB1 knockout (KO)) in BLCA cell lines resulted in the emergence of aggressive tumor growth leading to soft tissue metastasis to lungs, liver, kidney, and intestine in vivo. Mechanistic studies revealed that IL-6- STAT3 axis is upregulated in SMARCB1 KO BLCA cells. Our data suggest that the STAT3 specific inhibitor, inhibits invasive potential of SMARCB1 KO cells suggesting potential therapeutic efficacy for STAT3 inhibitor to treat subsets of BLCA harboring SMARCB1 loss. In addition, we identified a unique transcriptional signature activated upon SMARCB1 loss, which is predictive of poor patient outcome in BLCA, and hence may be clinically valuable. Citation Format: Chandra Sekhar Amara, Karthik Reddy Reddy, Yuntao Yang, Badrajee Waduge Danthasinghe, Allison Bellman, Andrea B. Apollo, David J. Shih, Leomar Ballester, Pavlos Msaouel, Wenjin J. Zheng, Matthew J. Ellis, Seth P. Lerner, Arun Sreekumar, Shyam M. Kavuri, Nagireddy Putluri. Elucidating the role of SMARCB1 in bladder cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2417.