title: Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice.
abstract: GNAQ and GNA11 are heterotrimeric G protein alpha subunits, which are mutated in a mutually exclusive pattern in most cases of uveal melanoma, one of the most aggressive cancers. Here we introduce the first transgenic mouse model of uveal melanoma, which develops cancers induced by expression of oncogenic GNAQ(Q209L) under control of the Rosa26 promoter. Disease penetrance is 100% by 3 months of age, with 94% of mice also developing lung tumors. In this model, the Yap protein of the Hippo pathway is activated in the eyes, and blood vessels near the lesions in the head and lungs exhibit melanocytic invasion. While full transcription levels are not necessary for GNAQ(Q209L) to transform mouse melanocytes, we obtained suggestive evidence of a selective advantage for increased GNAQ(Q209L) expression in human tumors. Intriguingly, enforced expression of GNAQ(Q209L) progressively eliminated melanocytes from the interfollicular epidermis in adults, possibly explaining the near absence of GNAQ(Q209) mutations in human epithelial melanomas. The mouse model also exhibited dermal nevi and melanocytic neoplasms of the central nervous system, accompanied by impaired hearing and balance, identifying a novel role for GNAQ in melanocyte-like cells of the inner ear. Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQ(Q209L) mutations contribute to both the initiation and metastatic progression of uveal melanoma.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jenny Li-Ying
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Oscar
authors.initials: O
authors.lastname: Urtatiz
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. cvr@mail.ubc.ca.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Van Raamsdonk
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness; D012880:Skin Pigmentation / Q000235:genetics; D014604:Uveal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D043802:GTP-Binding Protein alpha Subunits, Gq-G11