Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Abstract

<b>Background:</b> The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSC^med cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in <i>Pten</i>-deficient mice. The goals of this study were to assess the relevance of LSC^med cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. <b>Methods</b>: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSC^med cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. <b>Results</b>: LSC^med cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSC^med marker <i>Krt4</i>, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSC^med cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. <b>Conclusions</b>: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSC^med cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression.