Tenascin-C is an extracellular matrix molecule that drives progression of many types of human cancer, but the basis for its actions remains obscure. In this study, we describe a cell-autonomous signaling mechanism explaining how tenascin-C promotes cancer cell migration in the tumor micro-environment. In a murine xenograft model of advanced human osteosarcoma, tenascin-C and its receptor integrin alpha 9 beta 1 were determined to be essential for lung metastasis of tumor cells. We determined that activation of this pathway also reduced tumor cell-autonomous expression of target genes for the transcription factor YAP. In clinical specimens, a genetic sig-nature comprising four YAP target genes represents prognostic impact. Taken together, our results illuminate how tumor cell deposition of tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression. Significance: These results illuminate how the extracellular matrix glycoprotein tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression by employing integrin alpha 9 beta 1, abolishing actin stress fiber formation, inhibiting YAP and its target gene expression, with potential implications for cancer prognosis and therapy. (C) 2017 AACR.