YAP and TAZ have Functionally Redundant Roles in Uveal Melanoma

Uveal Melanoma (UM) is the primary ocular malignancy in adults. The primary tumor is treatable but 50% of patients develop fatal metastases. Most UM are driven by activating mutations in the heterotrimeric G protein alpha subunits paralogs, GNAQ or GNA11, whose main downstream effectors are MAPK signaling and the transcriptional activator YAP. Recent zebrafish work established the importance of YAP and de-emphasized the role of MAPK in UM. Here we show that deletion of yap has no significant effect on the incidence, or kinetics, of GNAQQ209L-driven zebrafish UM. Additional experiments revealed the presence of nuclear Taz in the yap null tumors. Our data suggest that this reflects functional redundancy between yap and its paralog, taz, either of which can efficiently drive UM. Furthermore, we show that the tumorigenic effects of YAP and TAZ are TEAD-dependent. To determine the human relevance, multiple YAP or TAZ-deficient clones were generated for two human UM cell lines, Mel202 and MP41. Deletion of either protein had no consistent deleterious effects on cell survival or proliferation, across the two cell lines in vitro. Moreover, deletion of YAP or TAZ did not prevent tumor formation in mice after intracardiac injection, and the clones show high liver tropism, modeling human UM metastases. The liver tumors displayed nuclear YAP and/or TAZ, as appropriate for their genotype, and only low-level, heterogenous staining for phospho-ERK. We conclude that the YAP/TAZ signaling plays the dominant role in both zebrafish and human UM, but most tumors can survive without YAP or TAZ due to the functional redundancy of these two proteins.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Biology

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2024

Author dc:creator

• Lamboy Rodríguez, Swanny A.

Advisor dc:contributor.advisor

• Lees, Jacqueline A.

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright retained by author(s)

Licence dc:rights.uri

• https://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/155388

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/155388