The increased aggressiveness of melanoma in elderly patients leads to increased metastasis and therapy resistance in these patients. Our goal in this proposed research is to understand the molecular mechanisms underlying age-related increases in melanoma metastasis, as well as effects on the immune microenvironment. Our overall hypothesis is that aged patients have changes in the extracellular matrix (ECM) of the skin that leads to differential motility of melanoma and the immune cells in the tumor. To test this hypothesis, we will undertake two specific aims that are outlined in the research proposal. The proposed studies are based on my findings from my previous studies that aging affects the metastasis in melanoma cells. My work identified various proteins that are de-regulated during aging, and our data showed a 35-fold decrease in levels of a collagen crosslinking protein, HAPLN1, during aging. Firstly, we will assess the effect of collagen crosslinking mediated by HAPLN1 on mediating the changes in migration of melanoma cells from the tumor. Secondly, we will focus on changes in the infiltration of lymphocytes into the tumor when age-related changes in HAPLN1 levels restructure the tumor ECM. We expect this research to generate targets for therapeutic implications in elderly melanoma patients. Apart from these goals, this NCI Predoctoral to Postdoctoral Fellow Transition Award will allow me to develop expertise in cancer research while providing me with funding to support my postdoctoral training. My training plan outlined in this proposal will take advantage of the extensive resources available to me at The Wistar Institute and University of the Sciences in the F99 phase of my training. During this phase, my training will be overseen by my mentor, Dr. Ashani Weeraratna who has successfully mentored several postdoctoral and clinical fellows in their academic careers.
Melanoma is an aggressive form of skin cancer that is more prevalent in individuals over the age of 50, and is very dependent on its interaction with other cells in the skin, such as fibroblasts. We have shown that changes in secreted factors from aged fibroblasts can increase the aggressive nature of melanoma cells, including factors which crosslink collagen, and hypothesize that the breakdown in collagen during aging facilitates the movement of melanoma cells. In this study, we will use state-of- the-art imaging techniques, as well as techniques such as the construction of artificial skin to understand how changes in the architecture of the skin during aging affect tumor progression and immune infiltration into the tumor in young vs. aged mice.
