Journal article
GNAQ Induces Melanomagenesis in Mitfa-Independent Melanocyte Progenitors in a Zebrafish Model of Uveal Melanoma
Cancer research (Chicago, Ill.), Vol.86(15), pp.3687-3703
08/01/2026
DOI: 10.1158/0008-5472.CAN-25-5299
PMID: 42269083
Abstract
Melanocytes reside in diverse microenvironments that influence their susceptibility to oncogenic transformation; however, investigation of rare melanoma subsets has been limited by the lack of suitable pre-clinical animal models. Here, we developed a primary, immune-competent zebrafish model to study uveal melanoma (UM) using choroidal melanocyte-targeted injection and electroporation of plasmids encoding human GNAQQ209L together with CRISPR/Cas9 cassettes for somatic tumor suppressor gene deletion. Single-cell transcriptional profiling of primary melanocytes and melanoma derived from the eye and skin revealed distinct transcriptional programs, with epithelial-to-mesenchymal transition pathways enriched in ocular tumors. In addition, choroidal fibroblasts from tumor-bearing eyes exhibited marked transcriptional changes, including increased fibronectin and collagen expression, consistent with stromal remodeling. Given prior associations between mitfa loss and accelerated GNAQQ209L tumor onset, the model was applied to determine whether melanocyte differentiation state contributes to the emergence of GNAQ-driven tumors. The increased susceptibility resulted from expansion of Mitfa-independent melanocyte progenitor populations in germline mitfa mutant zebrafish, rather than somatic mitfa loss in differentiated melanocytes, as conditional, melanocyte-specific mitfa deletion in adult zebrafish did not accelerate tumor growth. Furthermore, pax3a-positive melanocyte progenitor cells in mitfa-deficient zebrafish embryos and adult eyes and skin were highly susceptible to transformation induced by GNAQQ209L but not BRAFV600E. Analogous PAX3 positive populations were also identified in mouse and human single-cell transcriptomic datasets. Collectively, these findings establish a critical role for Mitfa-independent melanocyte progenitors in UM pathogenesis.
Details
- Title: Subtitle
- GNAQ Induces Melanomagenesis in Mitfa-Independent Melanocyte Progenitors in a Zebrafish Model of Uveal Melanoma
- Creators
- Julius I Yevdash - University of IowaDelaney Robinson - University of IowaRachel Moore - University of IowaZhijie Li - University of IowaKatelyn R Campbell-Hanson - University of IowaDanielle Gutelius - Boston UniversityStephen P G Moore - Boston UniversityDylan Friend - University of IowaIsaac O'Toole - University of IowaBrynnon E Harman - University of IowaCollin Montgomery - University of IowaRobert A Cornell - University of WashingtonAlexander Birbrair - University of Wisconsin–MadisonJesse D Riordan - University of IowaAdam J Dupuy - University of IowaElaine M Binkley - University of IowaRobert F Mullins - University of IowaDeborah Lang - Boston UniversityRonald J Weigel - University of IowaColin Kenny - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.86(15), pp.3687-3703
- DOI
- 10.1158/0008-5472.CAN-25-5299
- PMID
- 42269083
- NLM abbreviation
- Cancer Res
- ISSN
- 1538-7445
- eISSN
- 1538-7445
- Publisher
- AMER ASSOC CANCER RESEARCH
- Grant note
- National Cancer Institute (NCI): P30 CA086862 University of Wisconsin-Madison (UW): AAN4246 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): R01 AR062547 Melanoma Research Alliance (MRA): ID#1426690 Outrun the Sun (OTS): Honor of Doug Stickney National Institute of Dental and Craniofacial Research (NIDR): T90 DE023520 National Eye Institute (NEI): P30 EY025580 Division of Cancer Prevention, National Cancer Institute (DCP, NCI): R03 CA297549-01 U.S. Department of Defense (DOD): ME240045 LEO Fondet (LEO Foundation): LF-OC-21-000888 American Cancer Society (ACS): IRG-18-164-43 National Institute of General Medical Sciences (NIGMS): T32 GM144636
This work was supported by the Holden Comprehensive Cancer Center (P30 CA086862). Additional support to C. Kenny was provided by an institutional research grant from the American Cancer Society administered through the HCCC (IRG-18-164-43), the Melanoma Research Alliance (ID#1426690), and Outrun the Sun in honor of Doug Stickney. J.I. Yevdash and D. Robinson were supported by NIH predoctoral fellowships (T32 GM144636 and T90 DE023520, respectively). Additional NIH support was provided to C. Kenny (R03 CA297549-01), R.A. Cornell (R01 AR062457), R.F. Mullins (P30 EY025580), and D. Lang (R03 CA288281-01). Further funding was provided by the Leo Foundation (LF-OC-21-000888) to D. Lang, the Wisconsin Partnership Program (AAN4246) to A. Birbrair, and the US Department of Defense (ME240045) to A. Birbrair. The funders had no role in study design; data collection, analysis, or interpretation; manuscript preparation; or the decision to publish. All content was reviewed and approved by the authors, and artificial intelligence tools were not used in the design, conduct, analysis, or interpretation of the study.
- Language
- English
- Electronic publication date
- 06/10/2026
- Date published
- 08/01/2026
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; The University of Iowa Institute for Vision Research; Pathology; Surgery; Biochemistry and Molecular Biology; Ophthalmology and Visual Sciences
- Record Identifier
- 9985173066502771
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