Elucidating and Suppressing Cells of Origin of Cutaneous Melanoma
Abstract
Our proposal aligns directly with the Fiscal Year 2021 Melanoma Research Program Focus Area of Identify methods to decrease risk of melanoma development beyond sunscreen and protective clothing as it seeks to characterize the normal cells in which melanomas arise, and to test whether inhibiting them can prevent the changes that lead to melanoma formation. In doing so, this project will identify important targets for melanoma prevention and also treatments for early melanoma that prevent disease progression. Background: Melanoma is the fourth most common form of cancer and the most common cause of cancer-related death in young adults (20-50 years of age). Current prevention of melanoma is passive, relying on public health messaging to reduce ultraviolet (UV) light exposure from sun exposure and tanning beds, as well as early detection by doctors in high-risk patients. Unlike other cancers, there are no active treatments currently recommended for melanoma prevention. In part, this is because the events that lead to melanoma formation from normal, pigment-producing cells in the skin called melanocytes are poorly understood. Experiments performed by others and by us have suggested that only a small subset of melanocytes transforms to melanoma when exposed to UV light. One subset we have identified, which has increased levels of a protein called NTRK2, demonstrates such ability in that it can multiply after exposure to UV- irradiation, which appears to kill or damage other types of melanocytes without increased levels of NTRK2. If we could stop the proliferation of NTRK2-expressing melanocyte after exposure to UV light, this should reduce the risk of melanoma formation. Our work to date thus opens opportunities to better understand the cells from which melanomas arise and thence, to identify targets for therapies actively to prevent melanoma formation. What We Will Do: We already have some insights into this based on our preliminary experiments, and will test these using different laboratory models. In one model, we will create a new genetic modification in which the Ntrk2 protein is deleted in melanocytes. This will establish the role of this protein – which is known to be associated with cancer formation in other cells – in normal melanocyte functions such as maintenance of hair pigmentation, including during active hair growth. We will also be able to us the model to study in detail how the Ntrk2 protein might support melanocytes to respond to UV exposure. Another model is a well-established animal model wherein mice have genetic mutations commonly seen in human melanoma. These mice can be induced to develop melanomas, and we can study this induction closely to see how NTRK2-expressing melanocytes change as the mice develop melanoma, whether our already proposed preventive treatments might inhibit this development and, if any melanomas do occur, whether they are less likely to grow quickly and spread in the mice. Yet another model is newly developed in our laboratory, wherein we maintain pieces of human skin that have been donated by patients as left-overs from surgeries they have had. Under conditions we have developed, these pieces can survive for days outside the body, even following UV light exposure, allowing us to study changes in NTRK2-expressing and other melanocytes by a method called single cell RNA sequencing. This model also allows us to test whether our proposed treatments to inhibit NTRK2-expressing cells can do this in intact human skin that is exposed to UV light, including via application of topical treatments rubbed onto the surface of skin pieces in a manner that one might envisage an active, preventive treatment for melanoma being used in real-world conditions – just like sunscreens. Outcomes: Our experiments will provide new insights into the early changes that lead normal melanocytes in our skin to become melanomas. We will use this information to identify new approaches for inh
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210614
Entities
People
- Mark Shackleton
Organizations
- Monash University
- United States Army