Dissecting Integrated Cellular Programs Promoting Platinum Resistance and Progression in Bladder Cancer

PROJECT SUMMARY Platinum-based chemotherapy regimens improve survival for patients with muscle-invasive (MIBC) and metastatic bladder cancer (BC), and this approach remains the therapeutic cornerstone for this disease (and many solid tumor types). While we and others have begun to understand how certain molecular processes in MIBC tumors promote resistance, such as those involving DNA repair and immune microenvironmental transcriptional reprogramming, the diversity of these interacting properties and their mechanistic underpinnings are largely unknown. Our team’s advances in novel in vitro and in vivo bladder cancer model systems to enable direct interrogation of candidate mechanisms, when paired with patient-centered single cell and spatial profiling strategies (linked to advances in computational algorithms to dissect these data with tumor evolution principles), provides the preliminary insights and motivation to guide this hypothesis-driven proposal. Our overarching hypothesis is that distinct tumor and immune cellular programs cooperate to promote resistance to platinum chemotherapy in MIBC, and we can uniquely investigate this hypothesis through the following Specific Aims: 1) Define the influence of tumor-intrinsic cell cycle and DNA repair pathway alterations on platinum resistance in MIBC; 2) Dissect the impact of platinum exposure on macrophage reprogramming in MIBC; 3) Investigate mechanisms of tumor-macrophage crosstalk promoting platinum resistance in MIBC. For each of these Aims, we will perform directed mechanistic experiments using relevant BC models, and pair our unique clinically integrated patient cohort with integrative molecular analysis strategies (including whole genome, single cell, and spatial strategies directly implicated by our molecular hypotheses). Taken together, this hypothesis-driven proposal will define the relationship between specific tumor and immune cellular interactions in MIBC tumors that promote platinum resistance using a novel suite of functional, computational, and cross-disciplinary approaches. Broadly, this project will provide an integrative molecular, cellular, and experimental framework for understanding clinically and biologically relevant molecular underpinnings of tumor immune interactions and disease progression across tumor types.