Investigation of non-cell autonomous factors regulating sonic hedgehog target gene induction in skin

Basal cell carcinoma (BCC) is the most common skin cancer. It rarely metastasizes but is highly invasive and can cause extensive local tissue damage as a result. Tumors may represent a partial hair follicle lineage and all abnormally express Sonic hedgehog (Shh) target genes. Like developing hair follicles, BCC tumors display a striking reliance on adjacent stroma, suggesting that a non-tumor cell autonomous factor regulates tumor growth and/or Shh target gene induction in tumor epithelial cells. We have investigated two extracellular molecules and their role in BCC tumor biology.;We have also investigated the role of an epithelial-derived laminin, Laminin-511, in BCC growth and maintenance. Previously, Laminin-511 was found to be abundant along the basement membrane of hair follicles and to be required for hair follicle morphogenesis. Given the striking similarities between developing hair follicles and the growth of BCCs, we studied the role of Laminin-511 in several models of human BCC growth. We determined that Laminin-511 is required for maximal Shh target gene induction in human tumors. Furthermore, Laminin-511 and another epithelial laminin, Laminin-332, are required for tumor invagination in a xenograft model of BCC growth. In order to clarify the mechanism by which Laminin-511 functions in epithelial cell invagination, we are also studying the role of Laminin-511 in hair follicle morphogenesis. We have recently determined that Laminin-511 association with beta-1 integrin is not required in dermal cells for hair follicle development, so may be essential for epithelial cell signaling or association with the basement membrane. Continuing studies will address this requirement for Laminin-511 in developing hair follicle epithelium and will continue to instruct our knowledge on the regulation of processes necessary in BCC tumor biology.;The first, gremlin1, is a secreted BMP antagonist initially identified as a transcript overexpressed in BCC-derived dermal cells. Our investigations indicate that gremlin1 is expressed in BCC epithelial cells and therefore does not constitute a stromal-dependent signal. In addition, our in vitro and in vivo studies do not indicate a role for gremlin1 in the regulation of Shh target gene induction.