Defining the Role of Stem Cell Activation in Initiating Melanoma and Melanocytic Tumor Recurrence
Abstract
Melanoma is a lethal, aggressive cancer that causes the majority of skin cancer-related deaths in Caucasians, and incidence is on the rise. Recent reports indicate that the overall melanoma incidence in active military personnel is higher than in the general public. Additionally, members of the military recently deployed to Iraq and Afghanistan report excessive levels of sun exposure and sun burning, putting this population at high risk for melanoma. Melanoma is resistant to most traditional chemotherapies, but recent advances in newly designed targeted therapies have shown promise in extending lifespan for many with melanocytic tumors. Unfortunately, most patients eventually relapse and succumb to melanoma. Research aimed at preventing melanoma from arising in the first place or preventing relapse following treatment is underexplored, though this represents a potentially transformative avenue to change the total incidence of melanoma and decrease the number of mortalities caused by relapse. This proposal aims to address gaps in our knowledge of how melanoma tumors begin and how melanoma relapse occurs. A thorough understanding of how melanoma begins will provide the basis for the development of melanoma prevention strategies, which will benefit at-risk individuals that have been exposed to high levels of sunlight. Secondly, gaining insight on how melanoma tumors relapse will lay the foundation to prevent melanoma recurrence, which will benefit melanoma patients in remission. The experimental outcomes of this proposal will define the causes and conditions for melanoma initiation and recurrence and create molecular profile databases that capture the genetic changes occurring throughout the processes of initiation and relapse. Defining the conditions in a model system and generating these databases will provide a platform and resource from which our lab and others may identify and functionally test drug targets for prevention of melanoma initiation and relapse. In particular, this will ultimately benefit military personnel subjected to long-term sunlight exposure in the field and are thus at high risk for melanoma. Melanocytes normally function to protect skin from the ultraviolet radiation found in sunlight. Melanocyte stem cells represent a reservoir of adult stem cells that replenish melanocytes throughout the lifetime of an organism. Melanocyte stem cells can be activated by ultraviolet radiation or sunlight to generate melanocytes for protection. However, ultraviolet radiation is also a major risk factor that can transform melanocytes into melanoma cancer cells. Ultraviolet light causes DNA damage and inflammation in the skin, which is known to promote skin cancers. The first objective of this research proposal is to determine if melanocyte stem cell activation, by ultraviolet light exposure or by natural means, can act as a primary instigator that starts melanoma tumor growth in melanoma prone skin. By defining this process and identifying the molecular changes that occur, new strategies for preventing melanoma formation in tumor-prone skin will be developed. Due to the difficulty in treating existing melanoma tumors, prevention from first formation in tumor-prone skin presents a method with great potential for widespread benefit to military personnel and the general public. Within existing tumors, it is thought that a small population of non-dividing cells, called cancer stem cells or cancer propagating cells, evades therapeutic treatment and is at the foundation of tumor recurrence. The second objective of this proposal is to use an unbiased approach to identify cancer propagating cells within melanoma tumors that resist drug treatment and to delineate the molecular events that occur as these cells begin to form a relapsed tumor. Understanding how these cells begin the process of reforming a recurrent tumor can provide valuable insight that can be translated to new ideas for prevention of mela
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610272
Entities
People
- Andrew Dickson White
Organizations
- Cornell University
- United States Army