Abstract A41: Inhibition of aberrant YAP and TAZ activity to prevent metastasis formation and growth

Abstract

Abstract Metastasis causes most cancer-related deaths, and few effective therapies exist for patients with metastatic disease. The development of such therapies requires the identification of proteins essential for the spread and subsequent growth of metastatic cancer cells. Previous work from us and other groups has clearly demonstrated that aberrant YAP or TAZ activity, negatively regulated by the Hippo pathway, promotes cancer development and metastasis. Moreover, many human cancers have abnormally high YAP/TAZ expression or nuclear localization, and this is associated with poor prognosis. We hypothesize that targeting YAP and TAZ or upstream activators will prevent metastasis formation and growth, and we have developed and optimized in vivo model systems to test this. Using these methods, we show that YAP and TAZ are required for metastasis formation in human melanoma and breast cancer cells. An ongoing study using our in vivo metastatic growth assay and inducible YAP/TAZ RNAi is testing if YAP and TAZ are collectively required for metastatic growth after dissemination, and we hope to include the results of this study on our poster. In addition to directly targeting YAP and TAZ, we are also interested in identifying proteins that promote YAP/TAZ activity in metastatic cells, and this could lead to more therapeutic targets. Our recently published work shows that Src signaling can promote YAP/TAZ activity and enhance tumor growth and metastasis. Since integrins promote Src activity and regulate YAP and TAZ, we want to test if there are specific integrins required for YAP/TAZ activity in metastatic cells. Therefore, we used a YAP/TAZ-TEAD transcriptional activity reporter assay to perform an unbiased RNAi screen to identify integrins that regulate YAP/TAZ activity in metastatic melanoma and breast cancer cells. Knockdown of integrin subunits α2, α3, α6, and αV each reduced YAP/TAZ-TEAD transcriptional activity in metastatic breast cancer cells. These results have been confirmed with qPCR for the YAP/TAZ target genes CTGF and CRY61. Interestingly, a different set of integrin subunits appears to be required for YAP/TAZ-TEAD transcriptional activity in metastatic melanoma cells, suggesting the regulation of YAP and TAZ is not the same in different cancer types. Current work aims to use in vivo multiplex metastasis assays, which our lab has developed, to test if knockdown of each integrin either alone, or in combination, prevents metastasis formation and growth. Concurrently, we are focused on elucidating the mechanism by which these integrins enhance YAP/TAZ activity in metastatic cells. Collectively, these studies show the importance of YAP and TAZ and their upstream regulators in metastasis formation and growth and suggest that targeting YAP/TAZ activity may treat metastatic disease. Citation Format: Janine S.A. Warren, Emily Norton, John M. Lamar. Inhibition of aberrant YAP and TAZ activity to prevent metastasis formation and growth [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A41.