Melanoma, while composing only 1% of all skin cancers, causes the majority of skin cancer related deaths. In
the United States alone, over 100,000 new patients have been diagnosed with melanoma in 2021. While
plastic surgeons are frequently responsible for the oncologic reconstruction and removal of melanoma, few
surgeons in this field have the basic science training needed to understand the underlying molecular defects of
this condition or the dynamics of the mammalian epidermal microenvironment, in which they specialize. Such
knowledge is crucial for a holistic approach to the field of plastic surgery because the dysregulation of
intercellular communication between cells in this skin microenvironment, such as melanocytes, fibroblasts, and
keratinocytes, leads to various aesthetic and life altering defects such as those seen in vitiligo, keloid formation
and melanoma. We believe that a better understanding of developmental melanoblast migration can provide a
framework for future patient interventions and provide much needed context for future surgeons. This belief is
supported by recent studies in human melanoma, which show that the transcriptomic genetic profile of
melanoma cells closely mimic developmental melanoblasts. Second, it is well established that one of the
hallmarks of malignant melanoma is the loss of E-cadherin and upregulation of N-cadherin, but how adhesive
interactions between melanocytes and their surrounding keratinocytes via E-cadherin regulate melanocyte
behavior and homeostasis is not well understood. I hypothesize that melanocytes form specialized adhesions
with keratinocytes that serve to maintain the epidermal barrier while simultaneously promoting melanocyte
migration, colonization, and retention within the epidermis. I plan to test this hypothesis, by using the Cre-Lox
system under the control of a K14 epithelial promoter to selectively label melanocytes and knockout E-cadherin
in the keratinocyte microenvironment of the epidermis. I will then characterize the impact of disrupted
melanocyte-epithelial adhesions on melanocyte migration, protrusivity and colonization (Aim 1), identify the
composition and localization of melanocyte-epidermal adhesions and actin regulators (Aim 2) and determine
the impact of disrupted melanocyte-epithelial AJs on melanoma progression in a melanoma mouse model (Aim
3). This proposed project will be the first of its kind to characterize the impact of the surrounding keratinocyte
microenvironment on melanoblast migration and function; thus, seeing the epidermis as a complex
microenvironment with varying cell types, a biological reality that is often overlooked in medical training. This
proposed project and the training plan herein is designed to cultivate the necessary training to provide an
increase in translational research to the field of plastic surgery. This collaboration between Princeton University
and Robert Wood Johnson University Hospital Department of Plastic Surgery provides the clinical, basic
science training, mentorship, and resources necessary to accomplish this goal. It is our hope that this work will
be used to benefit patients with a history of melanoma worldwide.
