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Abstract

Melanoma is an aggressive tumor with a high degree of metastasis and limited therapeutic options. Yes Associated Protein 1 (YAP) and Transcriptional coactivator with PDZ-Binding Motif (TAZ) are transcriptional coregulators implicated in driving tumor progression and metastasis in a wide variety of cancers, including melanoma. While YAP and TAZ have historically been thought of to act in a redundant fashion, there is growing evidence from both developmental and cancer contexts that they may have both overlapping and unique functions of their own. As most prior studies on YAP and TAZ in melanoma have focused on both of the proteins simultaneously, it is currently unknown if YAP and TAZ are able to contribute to melanoma progression in unique fashions. In this dissertation I explored how YAP and TAZ drive melanoma growth, metastasis, and migration. I first identify that inhibition of YAP, but not TAZ, induces morphological changes in melanoma cells. Further functional assays reveal that YAP, but not TAZ, inhibition reduces melanoma cell numbers, ability to invade into matrigel, and numbers of focal adhesions. Using a non-biased RNA-sequencing approach, I demonstrate that YAP and TAZ regulate different transcriptomes in melanoma. Further analysis of the RNA-sequencing results revealed ARP2/3 complex member ARPC5 as a YAP specific downstream gene that regulates focal adhesion numbers and migration in our melanoma cell lines. These results lead me to propose a model in which YAP uniquely drives melanoma migration and focal adhesion numbers through regulation of ARPC5. As YAP and TAZ have been implicated to drive melanoma progression and metastasis, I also examined the effect that Verteporfin, a small molecule inhibitor that is actively used in the clinic for other purposes but was shown to inhibit YAP and TAZ transcriptional activity in vitro, has on melanoma cell initiation and progression in a transgenic melanoma mouse model (BrafCA; Tyr-CreERT2; Ptenf/f). While other groups found Verteporfin beneficial in the inhibition of tumor growth on xenograft models, I found no effect on melanoma initiation or progression in our transgenic mouse model using much lower, but clinically relevant, doses of Verteporfin. These results provide evidence that targeting both YAP and TAZ with Verteporfin may not be advantageous in melanoma. Additionally, these findings are significant and novel because it reveals that while higher doses of a small molecule inhibitor in xenograft models can seem to be a potential therapeutic, clinically relevant doses in model systems that better mirror disease progression may not have the same effect. Taken altogether, my studies provide evidence that YAP, but not TAZ, uniquely regulates melanoma cell progression and survival. Small molecule inhibitors that are YAP specific have promise as a less toxic and more beneficial strategy for fighting melanoma as both YAP and TAZ have been implicated to play redundant roles in tissue homeostasis and stem cell maintenance. Furthermore, my studies demonstrating that YAP and TAZ have vastly different functions in melanoma provide a foundation for future studies into how YAP and TAZ can differentially regulate downstream pathways.

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