Pattern formation in skin
Although site-specific differences in epidermal structures (such as hairs on skin) on different anatomic sites are easily appreciated and are the basis of many diagnostic and treatment strategies in skin diseases, embryologic transplantation experiments have demonstrated that it is the underlying mesenchymal stroma that dictates the epithelial fates that develop. We have begun to define the organizational and developmental principles of stromal cells based on their global gene expression programs.
For example, we discovered that endothelial cell (EC) diversity is primarily dictated by the vessel size of origin, and the Notch-Hey2 and left-right polarity signaling axis help to specify artery vs. vein fate. In contrast, fibroblasts from each anatomic site exhibit systematic and characteristic differences in gene expression and retain the embryonic anatomic expression pattern of Hox genes. Fibroblasts are thus excellent candidates as the bearer of positional memory in tissues and organs.
The unanticipated diversity and precision of fibroblast differentiation suggest much richer roles for stroma cells during development and diverse disease processes. Taking advantage of the unique capacities of skin for primary cell culture, gene transfer, and tissue reconstitution of site-specific features, we are pursuing the mechanisms by which the Hox code in fibroblasts specify epidermal fates, and how the embryonic Hox code is maintained in isolated adult fibroblasts.
A wound healing program in cancer metastasis
In contrast to the orderly acquisition of positional identities in development, cancer cells can abrogate and override the positional cues in tissues and organs as they metastasize. We discovered that one way that cancer cells may accomplish this feat is by activation of an emergency "wound healing" program.
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