Elucidation and Prevention of KIT-Mediated Melanomagenesis Using a Novel Multistage Murine Avatar
Abstract
Skin cancer remains a serious disease burden worldwide. The World Health Organization (WHO) estimates that 1 in 3 cancers diagnosed in the world is a skin cancer. About 3 million non-melanoma skin cancers and 132,000 cutaneous melanomas occur globally every year. In the United States, 1 in 5 Americans are expected to develop some form of skin cancer. Melanoma and other skin cancers are among the most common malignancies in military personnel. Moreover, studies of soldiers from World War II have shown a three-fold greater risk of melanoma among Pacific prisoners-of-war (POWs) compared to their European counterparts. In addition, Pacific and European POWs experience 3.4-fold and 2.8-fold more deaths from melanoma, respectively, compared to matched white U.S. men in the general population. While much has been published on sun exposure and melanomas, little is known about the etiology of sun-protected melanomas (those on the palms/soles and mucosal surfaces), which more often affect non-white individuals. These rarer melanoma variants are critically important as non-white military personnel have a 3.17-fold greater risk for melanoma compared to the civilian population. Within the broader U.S. cohort, the mean thickness (a direct measure of melanoma aggressiveness) of melanomas on sun-exposed sites, which predominantly occurs among whites, significantly decreased by 1.0% every 3 years while melanomas on the hands/feet significantly increased by 3.1% every 3 years. This has led to a significant decrease in mortality over this period for Whites but not for Blacks or Asian/Pacific Islanders. These are not recent trends. Multiple older studies have already described a notable disparity whereby melanoma survival among minorities appear to be significantly worse compared to whites. Thus, while excessive sun exposure and sunscreen use has been a cornerstone of prevention messaging for common sun-related melanomas, less is known about the etiology and pathogenesis of sun-protected melanomas with little resulting effort trained at its prevention and unique therapeutic vulnerabilities. The 2020 Melanoma Research Program has charged the scientific community to re-contextualize prevention through innovative tools and novel insights into melanoma tumor formation from the inciting cell to the lingering metastasis. This grant directly answers this call. One of the bottlenecks for more rapid gains in prevention and therapy among sun-protected melanomas is the lack of a veritable and malleable model to understand each of the stages of development. By creating a novel cellular model of sun-protected melanomas using the KIT oncogene, a cancer driver which is preferentially activated in acral and mucosal melanomas, we have established a quartet of cells which can recapitulate the biological milestones of cancer formation- transformation, tumorigenesis and immune escape. Using these new tools, we will attempt to unravel the etiological basis of KIT-driven melanomas and possibly define new paradigms in prevention and in treatment of acral and mucosal melanomas.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110872
Entities
People
- Hensin Tsao
Organizations
- Massachusetts General Hospital
- United States Army