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.