The NF1 Microenvironment: Friend or Foe?
Abstract
Neurofibromatosis type I is a genetic disease that affects around 1 child in 3,000. By the age of 20, most if not all patients will show characteristic skin lesions called neurofibroma and pigmentation defects (café-au-lait macules). These are the results of a hereditary mutation in a gene called NF1. Recently, scientists working on melanoma have found that the same NF1 gene is also frequently mutated. This is puzzling because melanoma patient very rarely develops the skin lesions and pigmentation defects typical of neurofibromatosis type I patients. Conversely, people that are born with a hereditary mutation in the NF1 gene very rarely develop melanoma. This indicates to us that the current model about the role of the NF1 gene in disease needs to be improved to clarify this discrepancy. I reasoned that the NF1 predisposing mutation of neurofibromatosis type I patients may actually have a protective effect on the development of some types of cancer (e.g., melanoma) in addition to its primary role where it favors the development of some other skin lesions (e.g., neurofibroma and café-au-lait macules). Experimentally, we test this new idea in the laboratory by comparing the rate at which characteristic lesions of neurofibromatosis type I form in mice that are genetically modified with the NF1 hereditary mutation. We discovered that, as seen in neurofibromatosis type I patients, mice with NF1 predisposing mutations develop characteristic lesions earlier than mice without predisposition. In addition, we observe that some mice without NF1 predisposing mutation ultimately develop cancer, whereas none of the mice with NF1 predisposing mutation develop any cancer within the same timeframe. Therefore, our new model states that the NF1 predisposing mutations promote the formation of a particular set of benign lesions characteristic to neurofibromatosis type I patients and at the same time is slowing down the development of some types of cancer. This discovery has a very profound and optimistic outcome for NF1 patients. For example, designing a drug that would interfere with the cell and the factors responsible for promoting the set of lesions characteristic to neurofibromatosis type I, or that would prevent any cancer formation, would be highly beneficial to NF1 patients. In this grant proposal, I will identify those cells and factors and make the demonstration, using a mouse model, that they are indeed critical for the development of the characteristic lesion of neurofibromatosis type I patients or cancer formation. This is a mandatory step in our quest to provide specific drugs to neurofibromatosis type I patients that either prevent the development of the set of lesions characteristic to neurofibromatosis type I or slow down any cancer formation. Following this validation step, medicinal chemists could begin to make drugs and systematically test them using our mouse model.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910238
Entities
People
- Jean-philippe Brosseau
Organizations
- United States Army
- University of Texas Southwestern Medical Center