Visualizing Early Acral Melanoma Initiation to Preclude Disease at Its Root

About This Grant

Summary: Acral melanoma is associated with a significantly lower survival rate compared to cutaneous melanoma. The goals of this study are to elucidate the early developmental stages of acral melanoma and to develop strategies to prevent its progression. A major barrier to understanding the progression of this deadly cancer lies in the paucity of preclinical models. Our lab recently developed a novel murine model that selectively targets mature melanocytes, thereby allowing for their precise manipulation within the basal layer of acral skin. We have demonstrated that these cells possess acral melanoma-forming capacity and can be used to model melanoma initiation at its earliest stages. This model overcomes a fundamental limitation of other existing models, which target immature melanocyte stem cells in skin appendages (hair follicles or sweat glands), as well as mature melanocytes. Building upon recently innovated technology from our lab, we can now visualize and track the emergence of acral melanoma from single epidermal melanocytes in real-time in vivo. This innovation has created new opportunities to address fundamental, yet unexplored questions in melanoma studies. In Aim1, we aim to answer the following key questions: 1) What percentage of melanocytes give rise to invasive melanoma when given mutations? 2) How many cell divisions occur prior to dermal invasion? 3) What melanoma cell density is required to disrupt the basal lamina? 4) Do melanoma cells invade as single cells or in `collectives? As we currently cannot prospectively identify melanoma-forming melanocytes in human samples before tumor formation becomes evident, our model is uniquely powerful in addressing these crucial questions. Moreover, our new live imaging platform for melanoma initiation has identified the essential role of Sortilin 1 (Sort1) in the initiation of acral melanoma. Sort1 is a cell surface protein known to promote migration and invasion in various cancers has been targeted for clinical trials because it is highly specific to tumor cells and may play an early role in tumor development. A potential function for Sort1 in melanoma has not been investigated. Our preliminary analyses identify Sort1 in early human acral melanoma, and inhibition of Sort1 significantly suppresses acral melanoma formation. Sort1 inhibitors have been actively studied in clinical trials, emphasizing the need to investigate their roles in melanoma. In Aim 2, we will investigate the function of SORT1 in both mouse models and human acral melanoma cell lines. We will investigate the molecular mechanisms underlying the effects of SORT1 inhibitor using spatial transcriptomic analysis. We will also utilize a xenograft assay to begin assessing the effects of its inhibition on a human acral cell line. Together, these studies will establish a framework for detecting its earliest invasive behavior and reveal SORT1 as a promising target for pharmacologic intervention to block melanoma progression at its inception.