A Noncanonical Frizzled2 Pathway Regulates Epithelial-Mesenchymal Transition and Metastasis
Menée sur des lignées cellulaires de cancer métastatique du sein, du côlon, du poumon et du foie, ainsi que sur des échantillons tumoraux et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels le récepteur Fzd2 favorise la transition épithélio-mésenchymateuse et le processus métastatique
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, noncanonical 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 and Wnt5a/b.