Epigenetic regulators of subtype plasticity in bladder cancer

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Project Summary/Abstract Bladder cancer can be subdivided into two categories: non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). NMIBC is treated by transurethral resection followed by either intravesical immunotherapy or intravesical chemotherapy, which have a 10-year disease-specific survival of 75%. In contrast, standard of care for MIBC is radical cystectomy with either adjuvant or neoadjuvant chemotherapy, with much lower disease-specific survival. However, approximately 20% of patients with high- grade NMIBC will progress to MIBC, and ongoing studies have been unable to determine the molecular mechanisms of this NMIBC-MIBC transition. Based on recent data from analyses of patient-derived bladder tumor organoids, we propose that NMIBC that is prone to progress is epigenetically distinct from stable NMIBC and transitions to MIBC through a mechanism of lineage plasticity. Specifically, a subset of organoids established from luminal NMIBC tumors undergo a phenotypic switch in culture to a basal/squamous phenotype, which is more typical of MIBC. Preliminary studies analyzing chromatin accessibility indicate that these phenotypically plastic patient derived organoids (PDOs) are epigenetically distinct from phenotypically stable PDOs. Furthermore, a chemical screen targeting epigenetic regulators in the phenotypically plastic organoid lines has revealed a key pathway governing phenotypic plasticity. Based on the hypothesis that phenotypic plasticity and epigenetic regulators promote the transition of NMIBC to MIBC, this proposed project will pursue two specific aims: (1) Map the chromatin accessibility and the histone modification landscape of phenotypic plasticity in NMIBC and validate these findings in human patient samples, and (2) Test whether the epigenetic regulators identified in a chemical screen can modulate plasticity in bladder cancer and determine whether these regulators are potential novel therapeutic targets. Combined, these two aims should lead to improved prediction of which high-grade NMIBCs will progress to MIBC and new therapeutics for treatment of high-grade NMIBC.