Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology
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nihms-952484.pdf
Description
Accepted version
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956.14 KB
Format
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Checksum (MD5)
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Author(s)
Perez, Dahlia E.
Henle, Andrea M.
Amsterdam, Adam
Hagen, Hannah R.
Lees, Jacqueline A.
Date Issued
March 2018
Journal
Pigment Cell and Melanoma Research
Publisher
Wiley
Citation
Perez, Dahlia E et al. "Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology." Pigment Cell and Melanoma Research 31, 5 (September 2018): 604-613 © 2018 Wiley
Version
Author's final manuscript
Abstract
Uveal melanoma (UM) is the most common primary intraocular cancer and has a high incidence of metastasis, which lacks any effective treatment. Here, we present zebrafish models of UM, which are driven by melanocyte-specific expression of activating GNAQ or GNA11 alleles, GNAQ/11 Q209L , the predominant initiating mutations for human UM. When combined with mutant tp53, GNAQ/11 Q209L transgenics develop various melanocytic tumors, including UM, with near complete penetrance. These tumors display nuclear YAP localization and thus phenocopy human UM. We show that GNAQ/11 Q209L expression induces profound melanocyte defects independent of tp53 mutation, which are apparent within 3 days of development. First, increases in melanocyte number, melanin content, and subcellular melanin distribution result in hyperpigmentation. Additionally, altered melanocyte migration, survival properties, and evasion of normal boundary cues lead to aberrant melanocyte localization and stripe patterning. Collectively, these data show that GNAQ/11 Q209L is sufficient to induce numerous protumorigenic changes within melanocytes.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1111/PCMR.12700
