A recent publication from Heinrich Kovar´s group at St. Anna Children´s Cancer Research Institute (CCRI) and colleagues reveals that inhibition of the YAP/TAZ pathway may prevent Ewing sarcoma cell dissemination and metastasis, thus presenting a promising new therapeutic target for a disease with a long-standing stagnant poor clinical outcome.
Verteporfin, a potent YAP/TAZ/TEAD complex inhibitor, reduced Ewing sarcoma cell migration and metastasis in a recent study of Lisa Bierbaumer, PhD student in the Molecular Biology of Solid Tumors group at St Anna CCRI. Therefore, she suggests: “YAP/TAZ inhibitors may be considered for combination therapy with cytotoxic standard-of-care chemotherapy to prevent onset of the metastatic cascade.” She adds, “Our study provides a proof of concept for the clinical promise of future drugs targeting YAP/TAZ with even higher specificity and improved safety features.”
What makes the YAP/TAZ/TEAD axis a potent target
Ewing sarcoma is a pediatric bone cancer with high and early dissemination potential and an overall survival rate of less than 30 percent for metastatic disease. The tumor is most commonly driven by the EWS-FLI1 fusion gene, inducing cell transformation and oncogenesis. Recent studies suggest that EWS-FLI1 may oscillate between high and low expression states, thereby orchestrating distinct phenotypic programs: Whereas cells with high EWS-FLI1 expression proliferate, cells that are low on EWS-FLI1 are migratory and invasive.
A prerequisite for the initiation of metastasis is the cell’s ability to transform from a highly organized into a loose, migratory phenotype. In the case of EWS-FLI1-low tumor cells, factors from the Hippo pathway are activated, a signaling cascade that controls organ size through the regulation of cell proliferation and apoptosis. In particular, TAZ levels are increased in the migratory EWS-FLI1-low state and are associated with adverse prognosis in Ewing sarcoma patients. This makes the YAP/TAZ/TEAD axis a potent metastasis target in this type of cancer.
Bierbaumer L, Katschnig AM, Radic-Sarikas B, Kauer MO, Petro JA, Högler S, Gurnhofer E, Pedot G, Schäfer BW, Schwentner R, Mühlbacher K, Kromp F, Aryee DNT, Kenner L, Uren A, Kovar H: YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells, Oncogenesis 2021 Jan 8;10(1):2. doi: 10.1038/s41389-020-00294-8.
Photo, f.l.t.r.: Heinrich Kovar, Lisa Bierbaumer; © Sebastian Seegy