The Hippo signaling co-regulators YAP and TAZ suppress invadopodia formation and matrix degradation in multiple cancer cells

Invadopodia are adhesive, mechanosensitive, actin-rich structures that integrate signals from the tumor microenvironment and play an important role in orchestrating tumor cell dissemination during metastasis. They possess extracellular matrix-degrading capabilities that expedite tumor cell invasion. Invadopodia also serves as a focal point for many signaling events that regulate tumor cell behavior. However, the precise molecular mechanism that governs invadopodia and drives cancer metastasis is currently unknown. Elucidating novel signaling pathways that drive invadopodia formation and tumor cell invasion may help comprehend the molecular events that regulate invadopodia in cancer metastasis. Here we studied the Hippo signaling co-regulator proteins YAP and TAZ and their involvement in invadopodia formation and matrix degradation. Systematic knockdown of YAP and TAZ showed a significant increase in invadopodia formation and gelatin matrix degradation in multiple cancer cell lines. In addition, treatment of cells with YAP/TAZ specific inhibitor verteporfin also increased invadopodia formation and matrix degradation. In contrast, overexpression of YAP and TAZ suppressed the invadopodia formation and matrix degradation phenotype significantly. A further investigation employing proteomic and transcriptomic profiling approaches revealed an upregulation of invadopodia-specific proteins and genes. We found that crucial invadopodia proteins Tks5 and MMP1-14 were upregulated upon the knockdown of YAP and TAZ. In conclusion, our study revealed that Hippo signaling co-activators YAP and TAZ negatively regulate invadopodia formation and matrix degradation in multiple cancer cell lines. This new finding may immensely help in understanding invadopodia-the key drivers of cancer metastasis-offering novel prospects on how to effectively target them in cancer therapy.