Identification of Genetic Mechanisms Driving Transition of Benign Nevi to Malignant Melanoma
Abstract
The Critical Problem: On average, cutaneous melanomas have among the highest mutation rates among human cancer. Despite this observation, benign melanocytic nevi show a remarkable genetic simplicity during disease initiation. The genetic analysis of moles (i.e., nevi) along with early-stage melanoma shows that the most well-studied drivers of cutaneous melanoma are present in benign nevi. Mouse models of melanoma also show that mutations in Nras or Braf along with inactivation of Cdkn2a efficiently produce benign nevi but don’t efficiently produce malignant melanoma. These findings suggest that additional mutations are required to drive progression from a benign to an invasive state. Unfortunately, it seems likely that the mechanisms of disease progression are diverse, likely involving many drivers. The most large-scale and comprehensive genetic analysis of melanoma identified 49 genes whose mutation is associated with melanoma. Most of these genes are presumed to be associated with disease progression since their mutation is not commonly seen in early-stage melanomas. The major issue is that these are generally less well characterized in melanoma. This leaves a tremendous knowledge gap regarding the biological mechanisms of melanoma progression. Understanding the mechanisms of progression at this critical transition point between benign and malignant disease could provide new therapeutic targets and/or strategies to treat invasive melanoma. The Objective of Our Proposal: The underlying premise of our proposal is that diverse genetic mechanisms drive the transition of benign nevi to malignant melanoma and that understanding these mechanisms will reveal new vulnerabilities that can be therapeutically exploited. Here we propose a novel, genetic screen to identify drivers of disease progression using a transposon mutagenesis method we have pioneered to build unique and novel models of the early stages of melanoma when cells convert from a benign state to an invasive melanoma. In addition, we will evaluate two poorly characterized genes (ZNF99, NEDD4L) that have been implicated in melanoma progression. However, the function of these genes has not been explored thoroughly in melanoma. In the case of ZNF99, our work would be the first attempts to study this protein. These experiments are important given that more than 15% of melanomas have mutations in ZNF99. Impact and Innovation: This proposal represents a new approach for my laboratory. Our prior melanoma research has focused on mechanisms of BRAF and MEK inhibitor resistance, a drug combination that is commonly used to treat approximately 50% of melanoma patients. We recently developed a new method to model melanoma in vivo using Sleeping Beauty transposon mutagenesis to accelerate the genetic characterization of the disease. We propose the use of the CBT melanoma model described this year in Science. This cell model is a valuable tool that we will use to perform a novel forward genetic screen to identify drivers of melanoma progression. Our proposal directly addresses the challenge statement by seeking to elucidate the earliest genetic events that drive the transition of melanoma from a benign or noninvasive form to invasive, metastatic disease. Understanding these mechanisms could provide insight into new therapeutic or prophylactic strategies to prevent or reverse melanoma progression. This application is focused on elucidating the genetic mechanisms that drive the transition of in situ melanoma to invasive disease. Relevance to the Mission of the Melanoma Research Program: This application is focused on elucidating the genetic mechanisms that drive the transition of in situ melanoma to invasive disease. Therefore, our proposed experiments directly seek to understand how precursor lesions and nvironmental/endogenous factors influence melanomagenesis. Part of our proposal will conduct a genetic screen to identify drivers o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310780
Entities
People
- Adam J. Dupuy
Organizations
- United States Army
- University of Iowa