GNAQ Induces Melanomagenesis in Mitfa-Independent Melanocyte Progenitors in a Zebrafish Model of Uveal Melanoma
Menée à l'aide d'un modèle de poisson-zèbre pour le mélanome de l'uvée et d'une analyse du profil transcriptomique de mélanocytes et mélanomes primitifs de l'oeil ou de la peau, cette étude identifie une sous-population de cellules progénitrices de mélanocytes qui est à la source de la mélanomagenèse induite par la protéine GNAQ et dont le programme transcriptionnel ne dépend pas du facteur de transcription Mitfa
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 preclinical animal models. In this study, we developed a primary, immunocompetent zebrafish model to study uveal melanoma 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 uveal melanoma pathogenesis.
Cancer Research , article en libre accès, 2026