Noncanonical FZD2 Signaling Induces EMT and Tumor Progression

Induction of epithelial–mesenchymal transition (EMT) by transcription factors, cytokines, or growth factors causes changes in cell morphology and motility and has been linked to tumor progression. Activation of canonical WNT/β-catenin signaling has been implicated in EMT; however, more recent findings suggest that noncanonical WNT5A ligands may also be upregulated during EMT, prompting Gujral and colleagues to investigate the mechanisms by which WNT5A contributes to EMT induction. Characterization of cancer cell lines from a variety of lineages and differentiation states revealed that expression of the WNT5A and WNT5B ligands and their cognate receptor Frizzled 2 (FZD2) was correlated with poorly differentiated, mesenchymal-type cancers and that FZD2 was frequently overexpressed in late-stage tumor samples. Functionally, depletion of FZD2 in cancer cells inhibited cell migration and invasion and reduced the expression of an EMT-associated gene signature via a mechanism that was independent of canonical WNT/β-catenin signaling. Screening of transcription factor reporters revealed that FZD2 interacted with and activated STAT3 and that inhibition of STAT3 reduced FZD2-mediated cell migration and EMT-associated gene expression. Using an unbiased kinome regularization assay, the SRC family tyrosine kinase FYN was identified as a potential mediator of FZD2 activity. Consistent with this idea, suppression of FYN reduced STAT3 phosphorylation and activity, decreased EMT-associated gene transcription, and inhibited FZD2-driven migration. Mechanistically, the SH2 domain of FYN mediated binding to phosphorylated Tyr552 of FZD2 and was required for STAT3 activation. Importantly, in support of FZD2 as a potential biomarker and therapeutic target, FZD2-specific neutralizing antibodies attenuated xenograft tumor growth and metastasis in vivo, and expression of FZD2 or an FZD2-associated gene signature was predictive of metastasis and poor survival in patients with hepatocellular carcinoma. Together, these findings highlight noncanonical FZD2-mediated signaling as an oncogenic driver of EMT and tumor progression and provide a rationale for exploiting FZD2 as a potential therapeutic target.

Gujral TS, Chan M, Peshkin L, Sorger PK, Kirschner MW, MacBeath G. A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell 2014;159:844–56.