Tenascin-C Downregulates Wnt Inhibitor Dickkopf-1, Promoting Tumorigenesis in a Neuroendocrine Tumor Model

• An immune competent, stochastic tumor model with high tenascin-C (TNC) is provided
• TNC has a decisive role in tumorigenesis by promoting early and late events
• TNC downregulates DKK1 expression through disruption of actin stress fibers
• TNC transgenic tumor mice are a model for human insulinoma and TNC targeting

SummaryThe extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC’s functions in cancer, we established an immune-competent transgenic mouse model of pancreatic β-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.

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