A GNAQ/11-driven zebrafish cancer model identifies MITF and YAP as key determinants for uveal melanoma

Uveal melanoma (UM) is a cancer of eye melanocytes that has a particularly poor prognosis and a dearth of treatment options. In contrast to cutaneous melanoma (CM), which is driven by oncogenic mutation of BRAF or NRAS, UM is driven by oncogenic mutations in GNAQ or GNA11 (>80% of patients). We developed a zebrafish model of UM by expressing GNAQ[superscript Q209L] in the melanocytes of p53-/- zebrafish. In this model, oncogenic GNAQ activates biological programs involved in pigmentation and tumorigenesis. The melanocyte lineage transcription factor MITF plays a well-defined role in CM tumorigenesis, wherein MITF expression is absolutely necessary for tumorigenesis and regulates proliferative versus invasive tumor phenotypes. In contrast, here we elucidated a novel tumor suppressor function for MITF in UM. In the context of oncogenic GNAQ, loss of mitfa accelerates tumorigenesis and reduces tumor reliance on p53 mutation.

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

2019

Author dc:creator

• Hagen, Hannah R.

Advisor dc:contributor.advisor

• Jacqueline A. Lees.

• Biology.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/122205

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/122205