Establishment of MITF and TAZ as major determinants of uveal melanoma

Abstract

Uveal melanoma (UM) is a cancer that arises from transformed melanocytes that exist in the uvea of the eye. Although UM is relatively rare, it is extremely deadly, due to the lack of treatment options for the metastatic disease. In contrast, cutaneous melanoma (CM), which is derived from transformed skin melanocytes, has multiple approved therapies, which have not worked in UM patients. Thus, there is great need to gain a deeper understanding of UM, and how it differs from CM, to inform effective therapeutic strategies. The vast majority of UM patients present with activating mutations in the GNAQ/11 pathway, which signals through PLCβ4-MAPK and YAP, whereas CM is primarily driven by activation of the MAPK pathway. It has been well established that CM tumors are dependent on MITF, the master melanocyte transcription factor. Here, in stark contrast, we establish that MITF serves as a tumor suppressor in an oncogenic GNAQ/11 UM zebrafish model. Moreover, we show that resulting MITF-deficient tumors are more de-differentiated and down-regulate PLCβ4-MAPK signaling, but retain active YAP. Furthermore, we establish that YAP, and not PLCβ4, is sufficient to drive MITF-wildtype tumorigenesis. Thus, our data de-emphasize the role of the PLCβ4-MAPK pathway in UM. We further show that YAP is surprisingly wholly dispensable for oncogenic GNAQ tumorigenesis in an autochthonous zebrafish model, but resulting tumors display active TAZ, a YAP paralog. Moreover, we establish that TAZ is an extremely potent oncogene in UM using autochthonous zebrafish models, even moreso than YAP. Furthermore, we show that higher TAZ expression, but not YAP expression, significantly correlates with decreased UM patient survival. Thus, this suggests that the role of TAZ does not entirely mirror that of YAP in UM. Lastly, we provide molecular characterization of the MITF-deficient state, and develop a system in which to screen UM therapies in vivo. Overall, our work establishes a tumor suppressor role for MITF, de-emphasizes the role of the MAPK pathway, and further underscores the importance of YAP/TAZ signaling in UM.