高分辨率空间转录组学揭示前列腺癌进展过程中肿瘤微环境的动态重塑

Prostate cancer exhibits diverse cellular composition, and the interaction between the tumor epithelial and tumor microenvironment (TME) cell types plays a crucial role in disease progression. However, due to technical limitations, systematic characterization of microenvironmental influences on prostate cancer progression remains insufficient. This study combined an assembled single-cell transcriptomic data (163 prostate samples; 756,000 high-quality cells) with the spatial data we obtained from 20 primary prostate tumors using the Visium HD platform to create high-resolution spatial profiles of the TME in prostate cancer. Our approach enabled detailed investigation of the dynamic remodeling of TME during prostate cancer progression from benign to low- and high-grade lesions. Our spatial transcriptomics data cohort includes 13 high-grade (grade group>=2) and 7 low-grade cases (grade group 1). We used the single cell clustering results as a reference and applied robust cell type decomposition (RCTD) to annotate the Visium HD data. In total, we identified 15 major cell types within the microenvironment and observed significant differences in the distribution of TME cell types and their frequency across benign, low-grade, and high-grade prostate cancers areas. Inflammatory fibroblasts and their gene signature were more prevalent in benign and low-grade microenvironments, whereas they decreased in high-grade TME. Conversely, myofibroblasts and their gene signature were enriched in high-grade TMEs. Within the smooth muscle populations, the more proliferative and migratory synthetic type (THY1-high) is increased in high-grade TMEs, while the contractile type (RERGL-high) was enriched in benign and low-grade microenvironments. Among endothelial cells, the abundant pro-angiogenesis subpopulation (EDNRB-high) was noted in high-grade TMEs, in contrast to the preferential enrichment of anti-angiogenesis subpopulation (RGS16-high), in localized to benign and low-grade microenvironments. Our findings uncover variations in the TME across tumor stages and implicate several important cell types that may influence prostate cancer progression, offering clues for future therapeutic exploration.