Bladder cancer progression from non-muscle invasive (NMIBC), particularly the T1 stage, to muscle invasive disease (MIBC) represents a critical clinical transition requiring aggressive therapy due to high metastatic recurrence risk. Risk of progression of T1 tumors is mainly based on the presence of invasive tumor cells breaching the urothelial layer and invading the lamina propria. However, cellular and molecular events occurring in the tumor microenvironment (TME) that drive this progression remain poorly defined. To address this knowledge gap, we investigated the changes within the TME associated with the progression of bladder cancer. Single-cell RNA sequencing (scRNAseq) analysis of untreated NMIBC and MIBC human samples, alongside multiplexed imaging, revealed extensive cancer-associated fibroblast (CAF) remodeling as a key feature associated with disease progression. We show that activated CAFs are present in small focal patches in T1 tumors that surround a subset of invasive tumor cells. Both cell types were more strongly associated with progression into MIBC than either population alone, supporting the interaction of these two cell types to promote tumor progression. I will address the implicated cross-talk using multiplex imaging, spatial transcriptomics, scRNAseq and in vitro assays. Overall, we highlight the importance of the stromal compartment and the cross-talk between specific populations of CAFs and tumor cells that may serve as a prognostic biomarker and therapeutic target in NMIBC.

Paris post-doc seminar series.