Metastatic progression of prostate cancer is mediated by autonomous binding of galectin-4-O-glycans to cancer cells
Metastatic prostate cancer (PCa) continues to pose a difficult therapeutic challenge. PCa progression is associated with aberrant O-glycosylation of cancer cell surface receptors, but the functional impact of such events are uncertain. Here we report spontaneous metastasis of human PCa xenografts which express high levels of galectin-4 along with genetic signatures of EGFR-HER2 signaling and O-glycosylation. Galectin-4 expression in clinical specimens of PCa correlated with poor patient survival. Galectin-4 binding to multiple receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt, fibronectin and Twist1, and lowered expression of E-cadherin, thereby facilitating epithelial-mesenchymal transition, invasion and metastasis. In vivo investigations established that galectin-4 expression enabled PCa cells to repopulate tumors in orthotopic and heterotopic tissues. Notably, these effects of galectin-4 relied upon O-glycosylation mediated by C1GALT1, a galactosyltransferase implicated in other cancers. Parallel changes in galectin-4 and O-glycosylation triggered aberrant receptor signaling and more aggressive invasive character in PCa cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal tumors. Our findings establish galectin-4 and C1GALT1-mediated glycosylation in a signaling axis that is activated during PCa progression, with implications for therapeutic targeting of advanced metastatic disease.