Dan Spandau, PhD
BS, Purdue University
MS, Indiana University
PhD, Indiana University
Awards and Professional Activities
Society for Investigative Dermatology
Sigma Xi, The Scientific Research Society
American Association for Cancer Research
National Scientific Advisory Committee, American Federation for Aging Research
Career Development Award, Dermatology Foundation
Glenn Foundation for Medical Research Scholar, American Federation for Aging Research
Henry M. Menn Memorial Award, The Skin Cancer Foundation
Former President, Indiana University Medical Center Chapter of Sigma Xi
As non-melanoma skin cancer (specifically squamous cell carcinoma and basal cell carcinoma) is predominately a disease of the elderly, we have become increasingly aware that biological age is an important risk factor for the development of skin cancer. Skin cells, or keratinocytes, are continually exposed to DNA-damaging ultraviolet radiation B (UVB) in sunlight. We have demonstrated that as keratinocytes age, they are less able to respond to the stress of UVB-irradiation. The inability of these geriatric keratinocytes to successfully control UVB-induced stress may contribute to the increased susceptibility of these keratinocytes to become malignant. The goal of our laboratory is to define the mechanism by which geriatric keratinocytes fail to respond to UVB-irradiation and to link this aberrant response to the incidence of skin cancer in the elderly. Currently, we are focusing on two major areas of research.
Insulin-like growth factor 1 receptor (IGF-1R)
Cell membranes of human keratinocytes contain the receptor for insulin-like growth factor-1 (IGF-1R). During normal cell growth, the activation of the IGF-1R leads to increased cell proliferation. However, following UVB irradiation, the function of the IGF-1R is drastically altered. UVB causes the IGF-1R to change from a receptor that signals mitogenesis to a receptor that signals survival. In addition to the survival signal following UVB irradiation, the activated IGF-1R also signals to inhibit cell proliferation thus preventing the passage of UVB-damaged DNA to daughter cells. If the IGF-1R is not active, UVB-damaged keratinocytes are capable of continued proliferation, perhaps leading to the development of skin cancer. In the skin, keratinocytes do not produce their own IGF-1 and are dependent on dermal fibroblasts to produce IGF-1. Unfortunately, as dermal fibroblasts age their production of IGF-1 declines. Therefore, aged epidermis is deficient in IGF-1 and this results in an inappropriate response of aged keratinocytes to UVB exposure. The effect of UVB on the IGF-R and the resultant changes in signal transduction pathways and their relationship to the development of skin cancer are currently being investigated in our laboratory.
Epidermal growth factor receptor family (erbB)
Key regulators of both the proliferative and differentiation signal transduction pathways in the skin are members of the erbB family of transmembrane tyrosine kinase receptors. Three of the four identified erbB family members are expressed in the keratinocytes of the skin, and many of their numerous ligands are either produced by keratinocytes or by cells that are adjacent to keratinocytes. The prototype of the family is the erbB1 protein, first identified as the epidermal growth factor receptor (EGFr) and also known as HER1. This protein is widely expressed in epithelial tissue, is most commonly associated with the induction of proliferative signaling and, has been extensively studied in a variety of cell types. The erbB2 protein, also known as neu or HER2, is frequently overexpressed in breast carcinomas. Less is know about the function of erbB2 in skin, but it has been suggested that expression and activation of the erbB2 receptor is associated with the induction of differentiation. Although the erbB3 receptor has been shown to be a critical signaling protein in other cell types, very little is known about the function of the erbB3 receptor in the skin. Data from our lab suggests that the erbB receptor family is integrally involved in the stress-response of keratinocytes induced by exposure to ultraviolet B radiation. We have made the following observations: 1.) UVB-induced apoptosis of human keratinocytes in culture requires functional erbB1 and erbB2 tyrosine kinase domains; 2.) Overexpression of the erbB3 receptor in keratinocytes renders the cells more sensitive to UVB-induced apoptosis. Because the erbB3 receptor is a substrate of both the erbB1 and erbB2 receptors but has little to no tyrosine kinase activity itself, these observations imply that the phosphorylation of the erbB3 receptor plays a critical role during the response of keratinocytes to UVB exposure. We are currently investigating the molecular, cellular, and tissue function of the erbB3 receptor in keratinocytes and human skin models during proliferation, differentiation, and UVB-induced stress response.