Identification of cancer-associated fibroblasts subtypes in prostate cancer

INTRODUCTION: Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types in tumor microenvironment. However, the phenotypic and functional heterogeneities among CAFs have not been sufficiently investigated in prostate cancer. METHODS: We obtained and analyzed the single-cell RNA-sequencing data from 26 hormone-sensitive prostate cancer samples and 8 castration-resistant prostate cancer samples, along with the analysis of bulk-sequencing datasets. Furthermore, we performed multicolor immunofluorescence staining to verify the findings from the data analysis. RESULTS: We identified two major CAFs subtypes with distinct molecular characteristics and biological functions in prostate cancer microenvironment, namely αSMA+ CAV1+ CAFs-C0 and FN1+ FAP+ CAFs-C1. Another single-cell RNA-sequencing dataset containing 7 bone metastatic prostate cancer samples demonstrated that osteoblasts in the bone metastatic lesions comprised two subtypes with molecular characteristics and biological functions similar to CAFs-C0 and CAFs-C1 in the primary tumor sites. In addition, we discovered a transcriptional factor regulatory network depending on CAFs-C1. CAFs-C1, but not CAFs-C0, was associated with castration resistance and poor prognosis. We also found that CAFs-C1 signature was involved in treatment resistance to immune checkpoint inhibitors. DISCUSSION: In summary, our results identified the presence of heterogeneous CAFs subtypes in prostate cancer microenvironment and the potential of specific CAFs subtype as therapeutic target for castration-resistant prostate cancer.