Abstract A015: Novel genetic driver for the genesis of muscle invasion in bladder cancer

Abstract Non-muscle invasive bladder cancer (NMIBC) is a heterogeneous type of urothelial carcinoma with a substantial risk (50%) of tumor progression and muscle invasion. Our sequential studies uniquely unveiled the availability of Retinal Degeneration Protein 3 (RD3) in human adult/fetal tissues and recognized its functional significance in tumor evolution. Herein, we investigated the relevance of RD3 in coordinating de novo MIBC from NMIBC. Compared to the low-grade tumor, RD3 is significantly lost (mRNA, qPCR; protein, ELISA) in grade III and IV patient derived NMIBC cells. In a cohort of (n=55) NMIBC patients, RD3-loss associated with increased tumor invasive potential (complete loss in highly invasive T4), metastasis (vs. primary tumors), therapy pressure (insignificant levels in progressive disease that defies therapy), disease recurrence, and death (custom archived TMA with automated RD3 IHC). Crucially, we observed a significant low-is-worse association to overall survival (p=7. 30E-03, hazard ratio (HR) of 5. 161), relapse-free survival (p=4. 464E-02, HR = 2. 328), and progression-free survival (p=7. 00E-0. 4, HR = 3. 264). Further, radio-resistant cells exposed to fractionated irradiation (FIR, 2Gy/Day for 5 days) to a total dose of 10 or 20Gy displayed a dose dependent loss of RD3 recognizing an ongoing acquisition of RD3-loss with therapy pressure. More interestingly, Grade I or III bystander cells (BSE) co-cultured with FIR-exposed cells displayed anew acquisition of RD3-loss and displayed tumor grade-dependent increase (vs. mock-irradiated) in NFkB transcriptional activity (EMSA) and the activation of NFkB trans-activated pro-survival molecules (QPCR profiling of 89 NFkB targets). Together, these results clearly depict that RD3 regulates NMIBC disease pathogenesis, dissemination, acquired loss of RD3 with therapy pressure and further implies its role in the evolution of de novo MIBC from NMIBC. Funding: DOD CA-210339, OCAST-HR19-045, NIH-P20GM103639, NIH-NCI-P30CA225520 and TSET-R23-03. Citation Format: Sreenidhi Mohanvelu, Poorvi Subramanian, Sabir Salim, Dinesh Babu Somasundaram, Sheeja Aravindan, Natarajan Aravindan. Novel genetic driver for the genesis of muscle invasion in bladder cancer abstract. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30 (10Suppl): Abstract nr A015.