Autocrine Activation of MAPK-Signaling Mediates Intrinsic Tolerance to Androgen Deprivation in LY6D Prostate Cancer Cells

The emergence of castration resistant prostate cancer is associated with a high mortality and remains an area of unmet clinical need. We recently identified a rare subpopulation of normal prostate progenitor cells, characterized by an intrinsic resistance to androgen-deprivation and marked by the expression of LY6D. We here describe the underlying mechanisms driving castration-resistance of LY6D+ luminal progenitors and their contribution to advanced prostate cancer. We demonstrate that conditional deletion of PTEN in the murine prostate epithelium causes an expansion of transformed LY6D+ progenitor cells in proximal and distal regions of the prostate without impairing stem cell properties. Transcriptomic analyses of LY6D+ luminal cells identified an autocrine positive feed-back loop, based on the secretion of amphiregulin (AREG), further increasing cellular fitness and organoid formation. Pharmacological interference with AREG-activated MAPK-signaling overcomes the castration-resistant properties of LY6D+ cells with a near complete suppression of organoid formation. Notably, LY6D+ tumor cells are enriched in prostate specimens from high-grade and androgen-resistant prostate cancer, providing clinical evidence for their contribution to advanced and also metastatic disease. Our data indicate that the prospective identification of LY6D+ cells could allow for an early interference with MAPK-inhibitors to prevent the emergence of castration-resistant prostate cancer.