A Noncanonical Frizzled2 Pathway Regulates Epithelial-Mesenchymal Transition and Metastasis

Abstract

SUMMARY Wnt signaling plays a critical role in embryonic development, and genetic aberrations in this network have been broadly implicated in colorectal cancer. We find that the Wnt receptor Frizzled2 (Fzd2) and its ligands Wnt5a/b are elevated in metastatic liver, lung, colon, and breast cancer cell lines and in high-grade tumors, and that their expression correlates with markers of epithelial-mesenchymal transition (EMT). Pharmacologic and genetic perturbations reveal that Fzd2 drives EMT and cell migration through a previously unrecognized, non-canonical pathway that includes Fyn and Stat3. A gene signature regulated by this pathway predicts metastasis and overall survival in patients. We have developed an antibody to Fzd2 that reduces cell migration and invasion and inhibits tumor growth and metastasis in xenografts. We propose that targeting this pathway could provide benefit for patients with tumors expressing high levels of Fzd2.

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts

“…We further demonstrate here that forced expression of Wnt7B increases both Wnt5A and α-SMA in hLFs and IPFFs. Evidence indicates that Wnt5A is elevated in lung cancer cell lines and drives both EMT and migration via the Frizzled2 receptor (Gujral et al 2014). The linkage between Wnt7B-Wnt5A expression in much of the vasculature of IPF lungs as a possible indicator of EnMT offers yet another potential mechanism for advancing the pathological growth and distortion of the pulmonary ECM.…”

“…(Vuga et al 2009). It is perhaps relevant that non-canonical Wnt5A signaling, an important characteristic of IPF (Willis et al 2006), regulates epithelial-mesenchymal transition (EMT) in metastatic lung cancer (Gujral et al 2014). It would not be surprising, therefore, that Wnt5A expression in IPF epithelial cells would play a contributory role in EMT processes that might add to the myofibroblast burden in IPF.…”

Planar cell polarity in moving cells: think globally, act locally

“…The downregulation of FZD6, DVL1, VANGL1, PK1 and WNT11 reduces protrusive activity and migration of breast cancer cells (BCCs), and PK1 is required to promote BCC metastasis in mice (Luga et al, 2012). Additionally, a link between FZD2, DVL1, VANGL1, SCRIB and WNT5A and cancer cell motility has been shown in several cancer cell lines (Anastas et al, 2012;Gujral et al, 2014;MacMillan et al, 2014;Yamamoto et al, 2010). A model for how PCP signaling regulates the migration of individual cancer cells has recently been proposed.…”

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

“…Increased FZD2 and WNT5A levels were measured in cancer cell lines, including CRC and advanced tumors, and were shown to promote epithelial-mesenchymal transition and metastasis. 50,51 FZD7 can enhance migration and invasion of CRC mediated by noncanonical WNT signaling. 50 PRICKLE1, a disheveled (Dvl) associated protein, may have a tumor suppressor function by antagonizing Dvl recruitment by Frizzled.…”