  Skin is one of the largest human organ systems whose primary purpose is the
protection of deeper tissues. As such, the skin must maintain a homeostatic
balance in the face of many microenvironmental and genetic perturbations. At
its simplest, skin homeostasis is maintained by the balance between skin cell
growth and death such that skin architecture is preserved. This study presents
a hybrid multiscale mathematical model of normal skin (vSkin). The model
focuses on key cellular and microenvironmental variables that regulate
homeostatic interactions among keratinocytes, melanocytes and fibroblasts, key
components of the skin. The model recapitulates normal skin structure, and is
robust enough to withstand physical as well as biochemical perturbations.
Furthermore, the vSkin model revealed the important role of the skin
microenvironment in melanoma initiation and progression. Our experiments showed
that dermal fibroblasts, which are an important source of growth factors in the
skin, adopt a phenotype that facilitates cancer cell growth and invasion when
they become senescent. Based on these experimental results, we incorporated
senescent fibroblasts into vSkin model and showed that senescent fibroblasts
transform the skin microenvironment and enhance the growth and invasion of
normal melanocytes as well as early stage melanoma cells. These predictions are
consistent with our experimental results as well as clinical observations. Our
co-culture experiments show that the senescent fibroblasts promote the growth
and invasion of non-tumorigenic melanoma cells. We also observed increased
proteolytic activity in stromal fields adjacent to melanoma lesions in human
histology. Collectively, senescent fibroblasts create a pro-oncogenic
environment that synergizes with mutations to drive melanoma initiation and
progression and should therefore be considered as a potential future
therapeutic target.
