Spatial transcriptomics reveals unexpected histological heterogeneity in primary prostate

Heterogeneity at different dimensions is a hallmark of prostate cancer (PCa). To carefully dissect the cellular and molecular landscape of PCa with distinct phenotypes, we conducted spatial transcriptomics (ST) and parallel single-nucleus RNA sequencing (snRNA-seq) technologies to identify areas of vulnerability amenable to therapeutic intervention. We here report the identification of an androgen receptor positive (AR+) but neuroendocrine-null primary PCa subtype with morphologic and molecular characteristics of small-cell carcinoma (SCLPC). snRNA-seq was performed on two samples representative of adenocarcinoma and SCLPC phenotypes, respectively. Further molecular characterization and wet experiments prioritized protein translation, represented by upregulation of many ribosomal proteins (RPs), and SP1, a transcriptional factor that drive SCLPC phenotype, as two potential therapeutic targets for treating AR-independent CRPC. Altogether, our studies reveal the non-rare existence of SCLPC in admixed PCa pathology, which may serve as a cell-of-origin for CRPC, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC. Overall design: Prostate biopsies from eight Chinese patients with histologically diagnosed PCa were collected. According to the manufacture's introduction, Visum spatial libraries were constructed using Visum spatial library construction kit (10x Genomics, PN-1000184). The libraries were finally sequenced using an Illumina Nova-seq 6000 platform.