Tumor cells appear more likely to metastasize if they are studded with too much Frizzled2, a kind of cell receptor, along with Wnt5, a signaling molecule that activates Frizzled2. The dangerous duo, say researchers at Harvard Medical School (HMS), may trigger a process long thought to be linked to cancer metastasis. This process, the epithelial-mesenchymal transition (EMT), is important in embryonic development, where certain cells must migrate, settle in new locations, and form new structures. In cancer, however, these cellular behaviors can wreak havoc.

The researchers were led by Marc Kirschner, Ph.D., John Franklin Enders University Professor of Systems Biology at HMS, chair of the Department of Systems Biology and Gavin MacBeath, Ph.D., lecturer in systems biology at HMS and senior vice president at Merrimack Pharmaceuticals. They not only discovered the importance of the Frizzled2 receptor, they also developed an antibody to block it.

The researchers described their work November 6 in the journal Cell, in an article entitled, “A Noncanonical Frizzled2 Pathway Regulates Epithelial-Mesenchymal Transition and Metastasis.”
“We find that the Wnt receptor Frizzled2 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 EMT,” wrote the authors. “Pharmacologic and genetic perturbations reveal that Fzd2 drives EMT and cell migration through a previously unrecognized, noncanonical pathway that includes Fyn and Stat3.”

In tissue samples from 48 cancer patients, Frizzled2 was higher in late-stage cancers than in early-stage cancers. And patients with late-stage liver cancer who had high levels of Frizzled-2 had lower survival rates.

In their paper, the researchers also indicated that their antibody reduced cell migration and invasion and inhibited tumor growth and metastasis in mice with certain types of tumors. The researchers are now pursuing further studies of the antibody with the hope that it can one day be turned into a metastasis-fighting drug.

“Frizzled2 provides a promising new therapeutic target to prevent or delay metastasis, and both Frizzled2 and Wnt5 are potential biomarkers that can be used to identify which patients are most at risk of metastasis and could benefit from Frizzled2-directed therapy,” said Dr. MacBeath.

In addition to exploring Frizzled2 as a new drug target, a potential biomarker for metastasis, and a possible addition to the factors that predict patient survival, the researchers look forward to identifying other pathway players to gain a full understanding of EMT in cancer and beyond.

“Although it will take time to determine whether this discovery can be translated into a novel therapeutic option for patients, I am very excited about the potential,” said Dr. MacBeath. “Significant advances in combating cancer must come from new approaches, and developing precision therapeutics that prevent metastasis provides a promising and different way to fight this devastating disease.”