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CAF\u2010conditioned medium induces the expression of sushi domain\u2010containing 2 (SUSD2) and enhances the invasive potential of pancreatic cancer cells. We showed that SUSD2 binds to integrin \u03b21 and promotes pancreatic cancer cell motility by inducing phosphorylation of focal adhesion kinase (FAK), facilitating the formation of focal adhesion complexes in cells adhered to collagen 1 or fibronectin. Orthotopic transplantation of SUSD2\u2010overexpressing human pancreatic cancer cell lines into the mouse pancreas enhanced liver metastasis in Panc\u20101 cells, whereas in KP2 cells, it increased primary tumor growth without promoting metastasis. In spheroid cultures of KP2 cells, forced SUSD2 expression elevated FAK phosphorylation independently of cell adhesion, suggesting that SUSD2 promotes cell proliferation even in non\u2010metastatic cells. 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