Sunday, May 5, 2013

Senescent fibroblasts can drive melanoma initiation and progression

A nice paper from our group (not me) recently posted on the arxiv.  Any comments are most welcome and will be passed directly to the authors.

Here is the link to the pre-print of:

Senescent fibroblasts can drive melanoma initiation and progression

By Eunjung Kim et al.

This is a collaboration between a theory group (Integrated mathematical oncology) and a wet lab (Smalley PI) and a great example of how a collaboration should work between theorists and experimentalists.

Melanoma is the most devastating form of skin cancer arising from the melanocytes, the pigment producing cells of the skin. Its initiation and progression is known to involve genetic changes in melanocytes as well as the disruption of both cell-cell and cell-microenvironment interactions. However, the mechanisms by which the deregulated interactions lead to melanoma development have been less understood. It is our view, that we must first model normal skin form and the regulatory mechanisms that maintain skin homeostasis before we can model cancer initiation. To this end, we developed a hybrid multiscale mathematical model of normal skin (virtual skin). The model focuses on key cellular and microenvironmental variables that regulate normal skin homeostasis. The model recapitulates normal skin structure, and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model revealed the important role of the skin microenvironment in melanoma initiation and progression. Experimentally, we found that as fibroblasts, an importance source of growth factors in the skin, become senescent their behavior changes significantly, leading to the expression of multiple growth factors, matrix proteins and proteases. We incorporated senescent fibroblasts into model to examine how microenvironmental changes affect skin structure. Our simulations showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing 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 showed 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. Based on our simulations combined with clinical data, we speculate that senescent fibroblasts may create a pro-oncogenic environment that cooperates with mutations to drive melanoma initiation and progression.{1304.1054}