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Oncogenic GNAQ and GNA11 Drive Tumorigenesis and Hyper‐Pigmentation in a Zebrafish Model of Human Uveal Melanoma
Author(s) -
Henle Andrea,
Hoelzli Emily,
Perez Dahlia,
Amsterdam Adam,
Lees Jacqueline
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb144
Subject(s) - gnaq , zebrafish , melanoma , cancer research , cancer , biology , carcinogenesis , mutation , genetics , gene
Uveal melanoma is the most common intraocular cancer, with an estimated 2000 cases diagnosed yearly in the U.S. Tumors arise from melanocytes in the choroid, iris, and ciliary body. Treatment typically includes proton beam therapy, and as such, the availability of tissue samples for research is limited. Approximately 50% of patients diagnosed with the disease develop untreatable liver metastases within 15 years. There is an urgent need to develop an animal model for uveal melanoma, in order to discover new therapeutics and understand disease initiation and progression.
Approximately 83% of human uveal melanoma tumors have activating mutations in GNAQ or GNA11. Signaling pathways known to cause cell proliferation and survival are active downstream of mutated GNAQ or GNA11, but the exact signals responsible for metastasis remain to be discovered.
We have developed a zebrafish model for human uveal melanoma by expressing mutated human GNA11 Q209L or GNAQ Q209L under control of the zebrafish melanocyte‐restricted mitfa promoter. Several lines have been identified that stably express either of the transgenes, Tg(mitfa:GNAQ Q209L ) or Tg(mitfa:GNA11 Q209L ) . These fish have been crossed to p53 M214K fish to facilitate tumor onset through a multi‐hit tumorigenic process. Tg(mitfa:GNAQ Q209L );p53 M214K and Tg(mitfa:GNA11 Q209L );p53 M214K zebrafish show hyper‐pigmentation in their skin and eyes. Fish develop tumors as early as 6 months of age. Our current efforts focus on the characterization of the tumors and the pigmentation defects. This model has revealed new mechanisms in pigmentation development and has provided insight into disease pathogenesis and metastasis.