CtBP2 triggers CCN1-induced metastatic dissemination of osteosarcoma cells in a non-hypoxic microenvironment

Osteosarcoma is the most prevalent pediatric solid bone tumor. These tumors are highly metastatic and frequently develop resistance to chemotherapy, leading to poor survival rate for patients. We found that C-terminal Binding Protein 2 (CtBP2) and Cysteine-rich protein 61 (CYR61/CCN1) expression level correlated positively in a panel of cell lines. In silico analysis of protein-protein interaction network revealed a link with stemness markers. We confirmed that CtBP2 influences stemness markers expression, cell clonogenicity, cell migration, matrix metalloproteinase activity and cell invasion. Surprisingly, using syngeneic tumor cells graft models, while induction of CtBP2 expression correlated with the metastatic dissemination process, it occurred only at the invasive front. Hypoxic conditions in central tumor region interfered with CtBP2 induction. Globally, we identify for the first time that CtBP2 is a required inducing factor in the CYR61-related metastatic progression of osteosarcoma. Moreover, we demonstrate that while CtBP2 is a downstream transcriptional target of CYR61 signaling cascade, it occurs only under non-hypoxic conditions. The present study suggests that CtBP2 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma.