Investigating the role of cell cycle plasticity in the growth and progression of bladder cancers

Cell cycle dysregulation is a fundamental driver of cancer progression, yet our understanding of cell cycle regulation remains largely based on a singular, canonical model. Recent technological advances have revealed that cells can execute distinct cell cycle programs - unique configurations of molecular networks that emerge from genetic and microenvironmental inputs. However, the prevalence and consequence of this cell cycle plasticity in cancer remain poorly understood. This study introduces cell cycle plasticity as a novel conceptual framework to understand bladder cancer heterogeneity. Using innovative single-cell spatial proteomics and machine learning approaches, we will map cell cycle programs across 661 bladder tumors spanning diverse histological and molecular subtypes. We hypothesize that bladder cancer cells execute distinct cell cycle programs that contribute to tumor progression and are shaped by the tumor microenvironment (TME). Through three integrated aims, we will: (1) catalog cell cycle programs driving bladder cancer growth and their association with histological/molecular subtypes, (2) investigate how specific TME configurations influence cell cycles using graph neural networks, and (3) develop experimental models that recapitulate cell cycle programs for mechanistic studies. This work will generate the first systematic catalog of cell cycle heterogeneity in bladder cancer and establish a publicly available resource of single-cell proteomic data mapping cell cycle effectors and TME biomarkers. Beyond advancing our fundamental understanding of bladder cancer biology, this study will provide a foundation for future biomarker discovery and therapeutic targeting strategies aimed at improving patient outcomes through precision oncology. Project Number: 1R21CA309329-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Wayne Stallaert (+1 co-PI) | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $412,856 | Activity Code: R21 | Study Section: Biochemical and Cellular Oncogenesis Study Section[BCO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11283824