YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Abstract

Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

Keywords: TAZ; YAP; hippo pathway; metastasis.

Figure 1

YAP/TAZ activation promotes several steps of the metastatic cascade. Depicted are the critical steps in the metastatic cascade. To spread tumor cancer cells (brown) undergo an EMT and then must invade through basement membranes and the surrounding tissue until they encounter a blood or lymphatic vessel. To intravasate they must then invade between endothelial cells (yellow). While in circulation, tumor cells interact with immune cells (blue) and platelets (orange). To seed distant organs, cells must arrest either by becoming lodged in small capillaries, or through active adhesion to the vessel wall, and then successfully exit the vessel (extravasation). To form a metastatic tumor, the cancer cell must survive and proliferate in a new microenvironment. Whether increased YAP/TAZ activity or decreased Hippo pathway activity promotes each of these steps is indicated. The direction of blood flow is indicated by red dotted arrows.

Figure 2

YAP/TAZ regulation by integrins and Src. Summarized are pathways that we discussed that influence YAP/TAZ activity downstream of Src or integrins. Pathways that activate YAP or TAZ are depicted as black lines, whereas inhibitory pathways are shown in red. Several of the integrin studies did not directly implicate FAK/Src signaling (indicated by FAK/Src? or Src?) but given what is known about integrin signaling cascades it is probable that they are involved.

Figure 3

Summary of discussed cancer-relevant pathways that activate YAP and TAZ. Depicted are several pathways that activate YAP and TAZ (black boxes/text) along with an indication of how each pathway is altered in cancer (red boxes/text). YAP/TAZ target genes implicated in cancer growth and progression (purple boxes/text) are also shown. Examples of existing drugs that target these pathways or are given (blue boxes/text).