Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology
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 predomin...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Wiley
2020
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| Online Access: | https://hdl.handle.net/1721.1/125206 |
| _version_ | 1811097813126217728 |
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| author | Perez, Dahlia E. Henle, Andrea M. Amsterdam, Adam Hagen, Hannah R. Lees, Jacqueline A. |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Perez, Dahlia E. Henle, Andrea M. Amsterdam, Adam Hagen, Hannah R. Lees, Jacqueline A. |
| author_sort | Perez, Dahlia E. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T17:05:21Z |
| format | Article |
| id | mit-1721.1/125206 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T17:05:21Z |
| publishDate | 2020 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/1252062022-10-03T10:20:56Z Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology Perez, Dahlia E. Henle, Andrea M. Amsterdam, Adam Hagen, Hannah R. Lees, Jacqueline A. Koch Institute for Integrative Cancer Research at MIT 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. National Institute of General Medical Sciences (Grant T32GM007287) National Cancer Institute (Grant P30‐CA14051) 2020-05-13T14:25:13Z 2020-05-13T14:25:13Z 2018-03 2017-10 2020-01-23T16:50:09Z Article http://purl.org/eprint/type/JournalArticle 1755-148X https://hdl.handle.net/1721.1/125206 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 en http://dx.doi.org/10.1111/PCMR.12700 Pigment Cell and Melanoma Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley PMC |
| spellingShingle | Perez, Dahlia E. Henle, Andrea M. Amsterdam, Adam Hagen, Hannah R. Lees, Jacqueline A. Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology |
| title | Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology |
| title_full | Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology |
| title_fullStr | Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology |
| title_full_unstemmed | Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology |
| title_short | Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology |
| title_sort | uveal melanoma driver mutations in gnaq 11 yield numerous changes in melanocyte biology |
| url | https://hdl.handle.net/1721.1/125206 |
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