Wnt2 expression in pancreatic CTCs promotes anoikis resistance and metastasis.
Major finding: Wnt2 expression in pancreatic CTCs promotes anoikis resistance and metastasis.
Clinical relevance: Inhibition of TAK1 kinase may prevent metastatic spread in pancreatic cancer.
Impact: Analysis of CTC expression profiles may reveal novel drug targets to suppress metastasis.
Circulating tumor cells (CTC) are shed into the circulation from primary tumors and likely give rise to metastases at secondary tissue sites; however, the molecular mechanisms involved in this process have not been well studied. Yu and colleagues describe a candidate signaling pathway important for CTC survival and metastasis in pancreatic cancer. Purified murine pancreatic CTCs were isolated using a microfluidic capture device and then subjected to single-molecule RNA-based sequencing. Comparison of this gene expression profile to that of primary tumors and normal pancreatic tissue yielded a set of genes with enriched expression in CTCs, including Wnt2. Overexpression of WNT2 in pancreatic tumor cells resulted in increased lung metastasis, suggesting that this protein may enhance the metastatic potential of CTCs. In support of this possibility, WNT2 expression promoted anchorage-independent tumor sphere formation and reduced anoikis. This prosurvival effect was likely mediated in part through fibronectin (FN1), which was required for WNT2-driven anoikis resistance, and noncanonical WNT signaling, which was elevated in murine pancreatic CTCs. In addition, inhibition of transforming growth factor β–activated kinase 1 (TAK1) decreased FN1 expression and reversed the WNT2 prosurvival phenotype, resulting in abrogation of both tumor sphere formation and metastasis, implicating TAK1 as a central mediator of WNT2 signaling. Importantly, WNT signaling may also be essential to bypass anoikis in human pancreatic tumor cells, as the expression of multiple WNT genes was induced under nonadherent conditions and activation of noncanonical WNT signaling was detected in a subset of patients with metastatic disease. These results support a role for the activation of noncanonical WNT signaling pathways in pancreatic cancer metastasis and identify TAK1 as a potential therapeutic target to suppress metastasis.