Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma
Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-12-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/71825 |
| _version_ | 1811227444945879040 |
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| author | Oscar Urtatiz Amanda Haage Guy Tanentzapf Catherine D Van Raamsdonk |
| author_facet | Oscar Urtatiz Amanda Haage Guy Tanentzapf Catherine D Van Raamsdonk |
| author_sort | Oscar Urtatiz |
| collection | DOAJ |
| description | Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract, or central nervous system. It is rare in melanomas arising in the epidermis. The mechanism for this specificity is unknown. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene. We found that GNAQQ209L, in combination with signaling from the interfollicular epidermis (IFE), stimulates dendrite extension, leads to actin cytoskeleton disorganization, inhibits proliferation, and promotes apoptosis in melanocytes. The effect was reversible and paracrine. In contrast, the epidermal environment increased the survival of wildtype and BrafV600E expressing melanocytes. Hence, our studies reveal the flip side of Gαq/11 signaling, which was hitherto unsuspected. In the future, the identification of the epidermal signals that restrain the GNAQQ209L oncogene could suggest novel therapies for GNAQ and GNA11 mutant melanomas. |
| first_indexed | 2024-04-12T09:42:37Z |
| format | Article |
| id | doaj.art-be10e9e67c4347a18cb5aa81f7f85055 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:42:37Z |
| publishDate | 2021-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-be10e9e67c4347a18cb5aa81f7f850552022-12-22T03:38:02ZengeLife Sciences Publications LtdeLife2050-084X2021-12-011010.7554/eLife.71825Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanomaOscar Urtatiz0Amanda Haage1https://orcid.org/0000-0001-6305-440XGuy Tanentzapf2https://orcid.org/0000-0002-2443-233XCatherine D Van Raamsdonk3https://orcid.org/0000-0002-4309-3513Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, CanadaDepartment of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, CanadaDepartment of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, CanadaDepartment of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, CanadaDifferent melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract, or central nervous system. It is rare in melanomas arising in the epidermis. The mechanism for this specificity is unknown. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene. We found that GNAQQ209L, in combination with signaling from the interfollicular epidermis (IFE), stimulates dendrite extension, leads to actin cytoskeleton disorganization, inhibits proliferation, and promotes apoptosis in melanocytes. The effect was reversible and paracrine. In contrast, the epidermal environment increased the survival of wildtype and BrafV600E expressing melanocytes. Hence, our studies reveal the flip side of Gαq/11 signaling, which was hitherto unsuspected. In the future, the identification of the epidermal signals that restrain the GNAQQ209L oncogene could suggest novel therapies for GNAQ and GNA11 mutant melanomas.https://elifesciences.org/articles/71825melanomasignalingepidermisoncogenePLCB4GNAQ |
| spellingShingle | Oscar Urtatiz Amanda Haage Guy Tanentzapf Catherine D Van Raamsdonk Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma eLife melanoma signaling epidermis oncogene PLCB4 GNAQ |
| title | Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma |
| title_full | Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma |
| title_fullStr | Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma |
| title_full_unstemmed | Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma |
| title_short | Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma |
| title_sort | crosstalk with keratinocytes causes gnaq oncogene specificity in melanoma |
| topic | melanoma signaling epidermis oncogene PLCB4 GNAQ |
| url | https://elifesciences.org/articles/71825 |
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