Molecular Mechanisms of Tumor Progression and Plasticity in Bladder Cancer

Endeavor Award (2020-Present)

Cory Abate-Shen, PhD, and Michael Shen, PhD, Columbia University - Principal Investigators

Cory Abate-Shen, PhD

Michael Shen, PhD

Bladder cancer is responsible for an estimated 17,000 deaths in the U.S. and nearly 200,000 deaths globally each year. Bladder cancer develops within the bladder lumen and can manifest as one of two forms. The more prevalent form, non-muscle invasive bladder cancer (NMIBC), usually has a better prognosis, whereas the less prevalent form, muscle-invasive bladder cancer (MIBC), is associated with poor clinical outcomes and greater lethality. These two types were once considered distinct diseases, but recent advances in genetic analysis and genetically engineered mouse models have revealed bladder cancer progression can occur across a continuum from NMIBC to MIBC. Additionally, studies have shown lineage plasticity, which defines a cell’s ability to change from one cell fate to an alternate cell fate, may play a central role in bladder cancer progression, and epigenetic reprogramming may serve as the critical mediator of tumor cell lineage plasticity.

Cory Abate-Shen of the Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University and co-investigators Michael Shen (HICCC), David Solit (Memorial Sloan Kettering Cancer Center), and David McConkey (Johns Hopkins School of Medicine) are conducting research to gain a better understanding of the molecular mechanisms regulating lineage plasticity in bladder cancer. By integrating clinical and translational medicine expertise across investigative teams and clinical sites, this team will interrogate the contribution of lineage plasticity to tumor progression and define the causal events driving progression from NMIBC to MIBC. A defining component of their research is an ambitious, team-science, multi-site plan to apply cutting-edge histopathological, genomic, and computational methods to the characterization of a first-of-its-kind prospective cohort of longitudinal bladder cancer samples obtained from patients whose cancer has progressed from NMIBC to MIBC. The Abate-Shen team expects learnings from their research will lead to better methods for identifying patients at elevated risk of progressive disease and improve clinical and economic outcomes by enabling new clinical trials and providing therapeutic options for better treatments of early-stage bladder cancer patients.

published research

Park S, Rong L, Owczarek TB, Bernardo MD, Shoulson RL, Chua CW, Kim JY, Lankarani A, Chakrapani P, Syed T, McKiernan JM, Solit DB, Shen MM, Al-Ahmadie HA, Abate-Shen C. Novel Mouse Models of Bladder Cancer Identify a Prognostic Signature Associated with Risk of Disease Progression. Cancer Res. 2021.

Warrick JI, Hu W, Yamashita H, Walter V, Shuman L, Craig JM, Gellert LL, Castro MAA, Robertson AG, Kuo F, Ostrovnaya I, Sarungbam J, Chen YB, Gopalan A, Sirintrapun SJ, Fine SW, Tickoo SK, Kim K, Thomas J, Karan N, Gao SP, Clinton TN, Lenis AT, Chan TA, Chen Z, Rao M, Hollman TJ, Li Y, Socci ND, Chavan S, Viale A, Mohibullah N, Bochner BH, Pietzak EJ, Teo MY, Iyer G, Rosenberg JE, Bajorin DF, Kaag M, Merrill SB, Joshi M, Adam R, Taylor JA 3rd, Clark PE, Raman JD, Reuter VE, Chen Y, Funt SA, Solit DB, DeGraff DJ, Al-Ahmadie HA. FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation. Nat Commun. 2022.

Clinton TN, Chen Z, Wise H, Lenis AT, Chavan S, Donoghue MTA, Almassi N, Chu CE, Dason S, Rao P, Rodrigues JA, Vasani NB, Ridouani F, Rosenberg JE, Bajorin DF, Teo MY, Bochner BH, Berger MF, Ostrovnaya I, Pietzak EJ, Iyer G, Gao SP, Hu W, Al-Ahmadie HA, Solit DB. Genomic heterogeneity as a barrier to precision oncology in urothelial cancer. Cell Rep. 2022.