Wnt5a-Fzd2 Noncanonical Wnt signaling
We uncovered a new non-canonical Wnt pathway through Frizzled2 receptor that drives EMT, cellular migration, and tumor metastasis. We show that among the large set of known Frizzled receptors and Wnt ligands, Fzd2 and Wnt5a/Wnt5b are selectively overexpressed in metastatic cancer cell lines and in high-grade human tumors, with high expression correlating with markers of EMT. Reducing receptor expression by RNAi or blocking receptor activity with anti-Fzd2 antibodies reduced Wnt5-mediated cell migration in vitro and inhibited tumor growth and metastasis in a mouse xenograft model.
Using a variety of systematic genetic and chemical tools, we dissected Fzd2 signaling in a panel of liver, breast, and lung cancer cell lines and showed that Wnt5a-Fzd2 binding leads to Stat3 activation, which in turn drives a pro-EMT transcriptional program. Using Kinome Regularization method (Gujral et al., PNAS), we identified the cytosolic tyrosine kinase Fyn as the key mediator of Fzd2-driven Stat3 phosphorylation. Fyn is recruited to a newly identified site of Fzd2 tyrosine phosphorylation and mediates activation of Stat3. Furthermore, a gene signature regulated by this pathway predicts metastasis and overall survival in patients. Finally, our findings are particularly significant because we show that the oncogenic activity of Fzd2 can be inhibited by an antibody –representing a new therapeutic strategy for treating metastatic disease.