Vitronectin enrichment in prostate cancer liver metastases promotes adhesion and survival.

The development of liver metastases in prostate cancer is associated with aggressive disease and poor prognosis. Because hepatocytes exhibit high metabolic activity with unique secretory profiles, we hypothesized that hepatocyte-to-tumor cell signaling plays a role in promoting liver metastasis. We evaluated single-cell transcriptomic data and metastatic tissue from patients with castration-resistant prostate cancer spanning androgen receptor (AR)-positive and AR-negative pathologies. Despite extensive intra- and inter-sample heterogeneity, communication analysis predicted vitronectin engagement of tumor integrins as a common feature. Vitronectin-positive hepatocytes were observed in prostate tumors with vitronectin accumulation in sinusoidal patches. Consistent with integrin activation, vitronectin treatment of AR-positive and AR-negative prostate cancer cells significantly promoted tumor cell adhesion, inhibited hypodiploid accumulation consistent with survival effects, and stimulated FAK-dependent phosphorylation of ERK and AKT. FAK inhibition with defactinib abrogated vitronectin- and serum-mediated adhesion in a cell-specific manner and mitigated VTN-driven depletion of hypodiploid populations. These findings support a model where dense intra-sinusoidal vitronectin deposits might capture metastatic prostate tumor cells in the liver and biochemically activate tumorigenic signaling, promoting tumor aggressiveness.