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Updated: Sep 24, 2025
Screening for Melanoma Modifiers using a Zebrafish Autochthonous Tumor Model
Published on: November 13, 2012
MITF deficiency accelerates GNAQ-driven uveal melanoma
Grace B Phelps1,2, Hannah R Hagen1,2, Adam Amsterdam1,2
1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Abstract:
Cutaneous melanoma (CM) and uveal melanoma (UM) both originate from the melanocytic lineage but are primarily driven by distinct oncogenic drivers, BRAF/NRAS or GNAQ/GNA11, respectively. The melanocytic master transcriptional regulator, MITF, is essential for both CM development and maintenance, but its role in UM is largely unexplored. Here, we use zebrafish models to dissect the key UM oncogenic signaling events and establish the role of MITF in UM tumors. Using a melanocytic lineage expression system, we showed that patient-derived mutations of GNAQ (GNAQQ209L) or its upstream CYSLTR2 receptor (CYSLTR2L129Q) both drive UM when combined with a cooperating mutation, tp53M214K/M214K. The tumor-initiating potential of the major GNAQ/11 effector pathways, YAP, and phospholipase C-β (PLCβ)–ERK was also investigated in this system and thus showed that while activated YAP (YAPAA) induced UM with high potency, the patient-derived PLCβ4 mutation (PLCB4D630Y) very rarely yielded UM tumors in the tp53M214K/M214K context. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(mitfa:GNAQQ209L);tp53M214K/M214K or Tg(mitfa:CYSLTR2L129Q);tp53M214K/M214K. Moreover, mitfa loss was sufficient to cooperate with GNAQQ209L to drive tp53–wild type UM development and allowed Tg(mitfa:PLCB4D630Y);tp53M214K/M214K melanocyte lineage cells to readily form tumors. Notably, all of the mitfa−/− UM tumors, including those arising in Tg(mitfa:PLCB4D630Y);tp53M214K/M214K;mitfa−/− zebrafish, displayed nuclear YAP while lacking hyperactive ERK indicative of PLCβ signaling. Collectively, these data show that YAP signaling is the major mediator of UM and that MITF acts as a bona fide tumor suppressor in UM in direct opposition to its essential role in CM.
Insights
Microphthalmia-associated transcription factor (MITF) acts as a tumor suppressor in uveal melanoma (UM), contrary to its role in cutaneous melanoma (CM). Loss of MITF accelerates UM development by promoting YAP signaling.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Cutaneous melanoma (CM) and uveal melanoma (UM) arise from melanocytes but have distinct drivers (BRAF/NRAS in CM, GNAQ/GNA11 in UM).
- Microphthalmia-associated transcription factor (MITF) is crucial for CM but its role in UM is unclear.
Purpose of the Study:
- To investigate the role of MITF in uveal melanoma (UM) development.
- To identify key oncogenic signaling pathways in UM using zebrafish models.
Main Methods:
- Utilized zebrafish models with patient-derived mutations in GNAQ or CYSLTR2, and tp53.
- Investigated the role of YAP and phospholipase C-β (PLCβ)–ERK pathways.
- Assessed the impact of mitfa deficiency on UM initiation and progression.
Main Results:
- GNAQ/CYSLTR2 mutations combined with tp53 mutations drive UM.
- Activated YAP strongly induced UM, while PLCβ mutations rarely did.
- Mitfa deficiency accelerated UM onset and progression, promoting YAP signaling and suppressing ERK activity.
Conclusions:
- YAP signaling is a major driver of UM.
- MITF functions as a tumor suppressor in UM, opposing its role in CM.
- Understanding MITF's role in UM opens new avenues for targeted therapies.
