Decoding Spatial and Cellular Heterogeneity in Recurrence of WTC-Related Prostate Cancer

Project Summary Prostate cancer rates are elevated among World Trade Center (WTC) responders, and some cases have unfortunately recurred and progressed to aggressive disease. While our team has conducted one of the first molecular profiling of WTC-related prostate tumors, current studies rely on bulk-tissue analyses, which overlook the contributions of specific cell types and spatial interactions in the tumor microenvironment (TME). This knowledge gap limits our ability to understand the mechanisms driving recurrence and impedes the development of targeted therapies. To address this challenge, the objective of this application is to uncover the molecular and cellular mechanisms driving prostate cancer recurrence in individuals exposed to World Trade Center (WTC) toxins. By leveraging spatial transcriptomics and multi-omics analyses, we will identify key regulatory pathways that differentiate recurrent tumors from those in remission in the spatial context of their TME. Our central hypothesis is that prostate cancer recurrence is driven by spatially localized dysregulation of genetic pathways and cellular interactions, e.g., DNA repair pathways and aberrant tumor-immune interactions specific to certain regions within the TME. The research team with complementary expertise in cancer epidemiology, genome technology, and cancer multi-omics will leverage several key innovations in this research project—including the use of (i) the Mount Sinai WTC tumor biobank, (ii) cutting-edge spatial transcriptomic technologies, and (iii) integrative computational pipeline for bulk/single-cell data—to resolve molecular drivers underlying the recurrence of WTC-related prostate tumors at spatial and cellular definitions. The technical feasibility and commitment of the research team are demonstrated by the strong preliminary data demonstrating our completion of Visium HD spatial profilings on one recurrent vs. non-recurrent WTC-related prostate tumor, which will be expanded to 20 primary WTC-related prostate tumors that recurred vs. achieved long-term remission in this study. The two Aims are: Aim 1. Identify Spatial TME Patterns associated with Recurrence in WTC-Related Prostate Tumors Aim 2. Determine the Genomic and Epigenomic Regulatory Drivers of Recurrence in Prostate Cancer This project is significant because it addresses a critical knowledge gap in understanding the recurrence of prostate cancer, particularly in WTC responders. By identifying spatially localized molecular mechanisms driving recurrence, the study has the potential to inform the development of targeted therapies, ultimately improving outcomes for WTC-exposed prostate cancer patients and broader patient populations at risk for aggressive, recurrent disease.