The stromal microenvironment as a co-organizer of bladder carcinogenesis and progression

OVERALL PROJECT SUMMARY
Bladder cancer (BC) is the second most common urologic malignancy affecting 573,278 people worldwide in
2020. Pathologically, BC is diagnosed as non-muscle-invasive (NMI) and muscle-invasive (MI) disease. Here
we define early bladder lesions as NMIBC. Major clinical gaps in NMIBC include i) lack of mechanistic insights
defining NMIBC progression, and ii) lack of platform for risk stratification of NMIBC that recur but never progress
(“non-progressors”), from those that progresses into MIBC (“progressors”) and consequently demonstrate poor
prognosis. The goal of our Center is to tackle this clinical issue by deciphering the underlying mechanisms
restraining or promoting the progression of early lesions (Project 1 & 2), and to leverage this novel biology as
candidate biomarkers to risk-stratify aggressive NMIBC (Project 3). This proposal seeks to shift the current
research paradigm in the field of NMIBC, by proposing a conceptually innovative tug-of-war between a tumor-
restraining (Project 1) and a tumor-promoting mechanism (Project 2) in determining the outcome of early bladder
lesions/NMIBC in becoming “progressors” or “non-progressors” (Project 3). Clinically, why “non-progressors”
often recur but seldom progress, and what are the driving forces advancing “progressors” into MIBC with poor
survival remain fundamental questions in field. Our tug-of-war hypothesis with two opposing forces is
conceptually different to most other studies, which primarily focus on one side of the coin. Further, the integration
of knowledge from Project 1 and 2 as a unified spatial proteomics and transcriptomics map by the Shared
Resource Core will reveal spatial and temporal relationships between distinct fibroblast populations with
opposing functions, their physical interactions with tumor and immune cell clusters, as well as their relationship
to the biomarkers from Project 3. Benchmark of success: The knowledge gained here will shift clinical practice
paradigm, by informing future NIMBC management through 1) the development of novel urinary profiling
strategies that could risk stratify aggressive NMIBC (Project 1-3); 2) the identification of targets for future
precision intervention, either by enhancing/sustaining the tumor-restraining mechanisms (Project 1) and/or
inhibiting the tumor-promoting mechanisms (Project 2). The overall success of our program is further ensured
by an extraordinary multi-investigator team that integrates three “organ-specific” bladder cancer investigators
within Cedars-Sinai Medical Center. All have active R01s and individual NCI-funding track record in performing
basic science research, translational bladder cancer research, or leading multi-center clinical trials on the
discovery and validation of biomarkers. Finally, they propose to collect valuable retrospective and prospective
NMIBC cohorts, which are essential to address the clinical questions posed within this proposal and will become
available to the research community as a shared resource to advance the field.

Grant Number: 5U54CA274375-04
NIH Institute/Center: NIH
Principal Investigator: Keith Syson Chan