Ongoing Research Projects
My laboratory has had a long-standing interest in studying genetic pathways required for normal skin development and in the identification of genetic alterations that occur in inherited skin diseases and in acquired skin diseases such as cancer.
The outer layer of the skin, the epidermis, is constantly renewed by adult epidermal stem cells, which persist throughout life. We have recently shown that epidermal stem cells are defective in some inherited skin diseases that exhibit fragile skin (Fig. 1). Our current research efforts are focused on developing methods to isolate and correct defective epidermal stem cells so that they could eventually be grafted onto patients with inherited skin fragility syndromes. Improved methods for the isolation and manipulation of epidermal stem cells could also be used for treating patients with chronic wounds or severe burns.
Figure 1. Schematic illustrating that epidermal stem cells are defective in epidermolysis bullosa simplex (EBS), but not in epidermolytic hyperkeratosis (EHK). Upon topical application of an inducer to the skin of K14-CrePR1/mtK14neo and K14-CrePR1/mtK10neo mice, respectively, the mutant alleles are activated by excision of the neo cassettes, thereby generating the dominant disease alleles (mtK14loxP, mtK10loxP). In the EBS model, the mutant K14 allele is not only activated in epidermal stem cells, but also expressed in these cells. Therefore, these cells are fragile and are replaced by non-phenotypic stem cells (mtK14neo) migrating in from the surrounding non-treated area. Although the neo-cassette is excised from the mutant K10 allele in stem cells, the gene is not expressed in stem cells, but only in the differentiated progeny of these cells in the suprabasal layers of the epidermis. Consequently, there is no selective pressure against stem cells containing the mtK10loxP allele. These stem cells persist and give rise to islands of mutant cells that result in persistent lesions for the life of the mouse.
With regard to genetic events that result in the development of skin cancer, we have used genetically engineered mouse models to show that the accumulation of genetic defects in epidermal stem cells eventually results in tumor formation (Fig 2). Furthermore, we have recently discovered that skin tumors themselves are maintained by defective stem cells, referred to as cancer stem cells. Our current research efforts are focused on isolating and characterizing cancer stem cells. An improved understanding of cancer stem cells could result in the development of novel therapeutic strategies that specifically target cancer stem cells for destruction and prevent tumor recurrence (Fig. 3).
Finally, we are also testing whether adult skin stem cells can be reprogrammed to form other cell types, such as neuronal cells.
Selected Peer-Reviewed Publications:
- Arin, M.J., Longley, M.A., Wang, X.J. and Roop, D.R. (2001) Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders. J. Cell Biol. 152: 645-649.
- Cao, T., Longley, M.A., Wang, X.J. and Roop, D.R. (2001) An inducible mouse model for epidermolysis bullosa simplex: Implications for gene therapy. J. Cell Biol. 152: 651-656.
- Waikel, R., Kawachi, Y., Waikel, P.A., Wang, X.-J., Roop, D.R. (2001) Deregulated expression of c-Myc depletes epidermal stem cells. Nature Genetics 28: 165-168.
- Koster, M.I., Kim, S., Mills, A.A., DeMayo, F.J., Roop, D.R. (2004) p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 18: 126-131.
- Sil, A.K., Maeda, S., Sano, Y., Roop, D.R. and Karin, M. (2004) IkappaB kinase-alpha acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428: 660-664.
- Caulin, C., Nguyen, T., Longley, M.A., Zhou, Z., Wang, X.J., and Roop, D.R. (2004) Inducible activation of oncogenic K-ras results in tumor formation in the oral cavity. Cancer Res. 64:5054-5058.
- Koster, M.I. and Roop, D.R. (2005) Asymmetric cell division in skin development: a new look at an old observation. Dev. Cell 9:444-446.
- Koster, M.I., Kim, S., Huang, J., Williams, T. and Roop, D.R. (2005) TAp63? induces AP-2? as an early event in epidermal morphogenesis. Dev. Biol. 289(1): 253-261, 2006.
- Koster, M.I., Lu, S.L., White, L.D., Wang, X.J., and Roop, D.R. (2006) Reactivation of Developmentally Expressed p63 Isoforms Predisposes to Tumor Development and Progression. Cancer Res. 66(8):3981-3986.
- Koster, M.I., Dai, D., Marinari, B., Sano, Y., Costanzo, A., Karin, M., and Roop, D.R. (2007) p63 induces key target genes required for epidermal morphogenesis. Proc Natl Acad Sci USA 104:3255-3260.
- Caulin, C., Nguyen, T., Lang, G.A., Goepfert, T.M., Brinkley, B.R., Cai, W.W., Lozano, G., Roop, D.R. (2007) An inducible mouse model for skin cancer reveals distinct roles of gain- and loss-of-function p53 mutations. J. Clin. Invest. 117:1893-1901.