Functional Role of Ras/MAPK Regulation of m6A in Melanoma Initiation and Progression
Abstract
Melanoma is the fifth most common cancer in the United States. Despite improvements in early diagnosis and advances in metastatic disease treatment, there is still a great need for innovative therapies to improve patients prognosis with primary resistance to checkpoint inhibitors and challenging subgroups. Cancer cells take advantage of alterations in gene expression to drive their altered behavior. RNA modifications represent a gene expression regulation mechanism that could be exploited to find novel therapeutic venues. m^6A is the most abundant mRNA modification. The enzyme responsible for this modification is METTL3. Several groups have recently implicated members of the RNA methylation pathway in various cancer types. Genetic alterations, including amplification and mutations, are found in METTL3. However, the upstream mechanisms that control the activity of METTL3 and its impact on melanomagenesis are poorly defined. The Ras/MAPK signaling pathway is critical for the initiation and progression of melanoma, and we found that ERK, a member of the RAS/MAPK pathway, phosphorylates METTL3. We, therefore, hypothesize that the ERK-mediated phosphorylation of METTL3, downstream of NRAS, alters METTL3 s functions. This altered METTL3 function would be required to achieve malignant phenotypes downstream of BRAF and NRAS to facilitate melanoma initiation and progression. We take up the Fiscal Year 2021 (FY20) Melanoma Research Program (MRP) Challenge by exposing a novel mechanism of regulation of melanomagenesis, the RNA modification m^6A, that could be used to prevent the initiation and progression of primary melanoma and block the development of micro-metastases. This novel pathway represents a paradigm shift of how common mutations responsible for melanoma achieve their malignant phenotypes by controlling RNA metabolic pathways, exposing new ways to target this malignancy. This proposal addresses two FY21 MRP Focus Areas: (1) Understand mechanisms that underlie metastatic spread to different sites, and (2) Delineate the molecular pathways that influence metastatic spread. To do this, we propose the following specific aims: (1) Establish the impact of m^6A RNA methylation on melanoma initiation and progression using a novel genetic mouse model, and (2) Define the oncogenic upstream mechanism of dysregulation of m^6A in melanoma. Thus, we propose to use a multidisciplinary approach, including the generation of a novel genetic mouse model, biochemical, molecular, cellular biology techniques to determine the role of the m^6A in melanoma initiation and progression. Understanding the basic mechanisms involved in the dysregulation of the RNA methylation process could lead to novel therapies to treat cancer and prevent and treat metastatic diseases. Thus, if successful, this application will provide the scientific foundations for the therapeutic targeting of m^6A methylation to prevent melanoma initiation and progression, which aligns with the vision of the MRP. Since m^6A is part of a general mechanism of gene expression regulation and the Ras/MAPK pathway is commonly altered, we expect that our findings will benefit most melanoma patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210823
Entities
People
- Claudio R. Alarcón
Organizations
- United States Army
- Yale University