PKA-driven SPP1 activation as a novel mechanism connecting the bone microenvironment to prostate cancer progression

Prostate cancer (PCa) bone metastasis (BM) poses a significant clinical challenge due to the heterogeneity of treatment responses and patient outcomes. In this study, we examined the role of Protein Kinase A (PKA) signaling in modulating the expression of osteopontin (SPP1/OPN), a protein associated with poor prognosis, within a subset of PCa BM patients. By integrating multi-omics results we identified a novel mechanism in which bone-derived type-I collagen (Col1a1) and fibronectin (Fn1) stimulate SPP1 expression in PCa cells through the activation of PKA signaling. This bone-induced regulation of SPP1 was confirmed both in vitro, using PCa-bone co-culture systems (PC3 or C42B/MC3T3 cell lines), and in vivo, using cell lines’ engraftments and patient-derived xenografts (PDX) grown intrafemorally. Importantly, clinical data from longitudinal patient samples revealed that treatment with enzalutamide, an androgen receptor (AR) inhibitor, led to an increase in PKA signaling and corresponding SPP1 expression in a subpopulation of patients, highlighting the relevance of the PKA/SPP1 axis in disease progression under AR-targeted therapies. Overall, we underscored the critical role of the bone microenvironment in influencing PCa progression, pointing out to SPP1/OPN as a biomarker for identifying tumors with active PKA signaling, which could serve to manage resistance to AR-directed treatments.