Distinct mesenchymal cell states mediate prostate cancer progression (human)
We sought to determine whether molecular alterations in tumor stroma influence prostate cancer progression and metastatic potential. To accomplish this, we compared mesenchymal cells from four genetically engineered mouse models (GEMMs) of prostate cancer representing different stages of the disease to their wild-type (WT) counterparts by single-cell RNA sequencing (scRNA-seq) and, ultimately, to human tumors with comparable genotypes. We identified 8 transcriptionally and functionally distinct stromal populations responsible for both common and GEMM-specific transcriptional programs. These are conserved between mouse models and human prostate cancers with the same genomic drivers. The transcriptional profiles of the stroma of murine models of advanced disease were similar to those of human prostate cancer bone metastases, with periostin expression by stromal cells influencing invasion and neuroendocrine differentiation. These profiles were then used to build a robust gene signature that can predict metastatic progression in localized disease independent of Gleason score. Taken together, this offers new evidence that the stromal microenvironment mediates prostate cancer progression. Overall design: Human prostate tissue specimens were obtained from patients undergoing radical prostatectomy at Weill Cornell Medicine. These included 9 samples; 3 ERG-negative and 6 ERG-positive cases.