DID YOU KNOW? DTIC has over 3.5 million final reports on DoD funded research, development, test, and evaluation activities available to our registered users. Click HERE
to register or log in.
A Microfluidic Method to Define the Role of Skin Microenvironment in Melanomagenesis
Exposure to environmental UV radiation (UVR) is considered a major etiological factor for skin cancer including malignant melanoma, the deadliest form of skin cancer. Since the ambient UVR exposure is greatest during midday hours, tasks such as long periods of training exercises for soldiers or sailors can influence the daily UVR exposure. Deployment of military personnel over the past decade in countries with near maximum annual averages of solar radiation potentially increases their risk of melanoma. Mutations in genes (specifically NRAS and BRAF) that activate mitogen activated protein kinase signaling are the major drivers of cutaneous melanoma and found in >80% melanomas. Majority of nevi, which are collections of growth arrested melanocytes, also harbor mutations in BRAF, but do not necessarily act as precursors of melanoma. A widely accepted explanation for this observation is that melanocytes that acquire oncogenic mutations proliferate transiently and then are growth arrested due to oncogene-induced senescence (OIS), which acts as barrier to melanoma development. Bypass or escape from OIS is thought to be responsible for melanoma tumor development from BRAF-transformed melanocytes. Efforts to validate the OIS model produced conflicting data. While investigations were primarily focused on genetic and epigenetic events within melanocytes, the role skin microenvironment plays in OIS is poorly understood. The overall goal of this project is to understand the role of melanocyte microenvironment in melanoma tumor development. We hypothesize that cellular contact with UV exposed epidermal keratinocytes and/or secreted factors from other skin-resident cells influence OIS-escape and malignant melanoma tumor development. Genetic mouse models and co-culture of isolated human skin cell, although useful, have several limitations. Microfluidic methods offer powerful and versatile alternative to overcome the limitations of these approaches.
Approved For Public Release