Castration-induced SPARC down-regulation in stroma cells drives neuroendocrine differentiation of prostate cancer

Fatal neuroendocrine (NE) prostate cancer evolves from castration-resistant adenocarcinoma as a mechanism of resistance to androgen deprivation/anti androgen receptor therapies. Evidence suggests the microenvironment as a possible source of soluble factors mediating neuroendocrine differentiation (NED), but molecular mechanisms are unknown. Using a transgenic mouse model we show that upon castration tumor cells up-regulate GRP78, which triggers a cascade leading to down-regulation of the matricellular protein SPARC in the nearby stroma. SPARC loss allows stroma cells to release IL-6, a known inducer of NED. A drug targeting GRP78 blocks NED in castrated mice. These events find correlation in prostate cancer patients developing focal NED after androgen deprivation therapies. Our results candidate SPARC and GRP78 for diagnostic and therapeutic purpose, respectively. Overall design: RNA-sequencing was performed on T23 adenocarcinoma cells, in different co-culture conditions. Samples were analyzed in triplicate.