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Defining the role of MAFG in melanocyte transformation and melanoma development

Award Number: R01CA299434
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Defining the role of MAFG in melanocyte transformation and melanoma development - PROJECT SUMMARY Over the past decade, non-genetic mechanisms have emerged as powerful drivers of melanoma initiation and progression. These mechanisms include epigenetic, transcriptional, and post-transcriptional alterations that lead to dynamic and reversible changes in gene expression programs. Among these, the deregulation of transcription factors plays particularly potent roles in melanomagenesis, and we have identified the transcription factor MAFG as a critical player in melanoma development. MAFG exhibits increased expression levels in human melanoma and promotes the oncogenic behavior of melanoma cells. Additionally, overexpression of MAFG in a genetic mouse model of melanoma dramatically accelerated melanomagenesis. Conversely, genetic deletion of MAFG in a genetic mouse model of aggressive melanoma completely prevented the transition from nevi to frank melanomas, indicating MAFG’s critical role during tumor initiation. The oncogenic function of MAFG may, in part, be mediated by a phenotype switch and an interaction with the lineage transcription factor MITF. We hypothesize that MAFG acts as both a potent driver and a specific vulnerability in melanoma, making it a promising target for therapeutic intervention. However, critical questions remain about the cell biological and molecular influence of MAFG on melanomagenesis, which we will address in this proposal. Aim 1 will uncover the role of MAFG in melanocyte transformation and melanomagenesis. Using our ESC-GEMM platform, we will comprehensively evaluate MAFG’s role in melanocyte transformation, melanoma initiation, malignant progression, and metastasis across various genetic contexts. This Aim seeks to establish the foundational impact of MAFG in melanoma development. Aim 2 will decipher the oncogenic mechanisms of MAFG through its binding partners. We will investigate how MAFG cooperates with MITF to drive melanomagenesis and determine if MITF is required for the oncogenic effects of MAFG. Moreover, we will determine if the canonical binding partner BACH2 cooperates with MAFG to drive melanoma. This Aim will elucidate the molecular pathways by which MAFG exerts its oncogenic effects, focusing on its interaction with key transcriptional regulators. Aim 3 will define the vulnerability of melanoma to MAFG depletion. We will assess the molecular consequences of acute MAFG depletion in melanoma and perform a CRISPR screen to identify actionable upstream regulators of MAFG. This Aim will uncover potential therapeutic targets by highlighting the dependency of melanoma cells on MAFG. By addressing these Aims, our studies will provide critical insights into MAFG’s role in melanoma biology and pave the way for novel therapeutic strategies targeting MAFG and its downstream pathways. This work holds significant potential for improving outcomes for patients with metastatic melanoma, a currently intractable malignancy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $607,249 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Cause and Prevention Research	000	1	4/6/2026	NEW	$607,249
														Subtotal = $607,249

Grand Total All Awards = $607,249

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Defining the role of MAFG in melanocyte transformation and melanoma development

Award Number: R01CA299434

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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