Unraveling RNA modifications dynamics in prostate cancer progression and spatial tumor-immune interactions at single-cell resolution
Ana Añazco Guenkova
Centro de Investigación del Cáncer. Universidad de Salamanca - CSIC
Prostate cancer (PCa) is the most prevalent cancer among men and the second most diagnosed worldwide. While initial responses to conventional therapies are often positive, advanced PCa frequently leads to metastasis and therapy resistance. Immune checkpoint blockade (ICB) has shown promise in treating tumors; however, the immunosuppressive tumor microenvironment (TME) in PCa limits its efficacy. In this sense, epigenetic inhibitors have demonstrated potential in reprogramming immune cells towards a tumoricidal phenotype. The analysis of The Cancer Genome Atlas (TCGA) databases revealed significant alterations in RNA modifying proteins (RMP), known to influence tumor progression. Applying deconvolution methods, we found an inverse correlation between RMP expression and immune cell infiltration. Despite this, no RMP signature has been directly linked to PCa advancement. In this study, we aim to elucidate the role of RMPs in PCa progression and their interaction with immune cells. Using single-cell RNA sequencing (scRNA-seq) and multiplex imaging to analyze different disease stages, including castration-resistant PCa (CRPC) in a mouse model, we observed significant cellular dynamics. During PCa progression, post-castration hormone-dependent epithelial cells diminished, whereas a hormone-independent pre-existing subpopulation, including the periurethral (PrU) population, proliferated more. When studying epithelial-immune cell interactions, we observed significantly increased interactions between the PrU population and immune cells in tumorous stages compared to healthy ones, which correlates with a higher immunosuppressive microenvironment. This and other hormone-independent populations exhibit a dynamic expression of several RMP along cancer progression. These findings underscore the complex interplay between RMP-expressing cells and immune cells in PCa. Our comprehensive analysis of cellular heterogeneity provides critical insights into PCa progression and treatment response, emphasizing the potential of targeting RMPs for advanced therapeutic strategies.