Stephen Lyle earned his B.A. and M.S. in Biology and Biochemistry from the University of Chicago in 1988. He completed the M.D./Ph.D., program at the University of Chicago Medical School in 1995. From 1995-99, Dr. Lyle was an Anatomic Pathology resident at The University of Pennsylvania Hospital, and also conducted post-doctoral research in the Department of Dermatology. He then completed the 1-year fellowship in Dermatopathology at Harvard Medical School before joining the faculty at Beth Israel Deaconess Medical Center. He was an assistant professor of pathology and associate director of the Dermatopathology Fellowship at Harvard until 2005 when he became a member of the UMass Cancer Biology faculty and Director of the UMass Cancer Center Tissue Bank.
Adult Epithelial Stem Cells
Research in the Lyle laboratory focuses on the molecular and cellular characterization of adult epithelial stem cells and pathways which lead to cancer from stem cells. We have identified a number of differentially expressed genes within the stem cell compartment and we are investigating the functions of these genes in mediating stem cell properties such as self-renewal, growth, differentiation, adhesion and migration. The goals are to characterize genes which define the stem cell phenotype and identify critical pathways that mediate stem cell behavior and function. We are also addressing two important questions regarding stem cells and cancer; 1) do cancers arise from adult stem cells, and if so, what are the molecular mechanisms which transform a stem cell?, and 2) do cancers themselves have stem cells, termed “cancer stem cells”, which are responsible for tumor growth, recurrence and metastasis?
Stem Cell Genes
Building on our earlier identification of the skin stem cell niche and the discovery of the keratin 15 stem cell marker (Lyle et al., J Cell Sci. 1998;111, 3179-88), we have been interested in characterizing other functional genes within stem cells. In a screen of differentially expressed genes, we identified a number of genes which are up-regulated in stem cells. One of the genes we have been studying, the dual-specificity kinase CLK1, shows striking co-expression in the stem cell compartment (Figure 1). Using a number of in vitro assays of stem cell behavior, we are investigating the role of CLK1 in mediating the stem cell phenotype. In addition, to CLK1, other known differentially expressed genes are beginning to be examined.
Unique Stem Cell Factor
Earlier we showed that the stem cells of skin resided in a specific area of the hair follicle called the "bulge". We and others have shown that these cells have stem cell properties of self-renewal, slow-cycling and multi-potentiality within skin, giving rise to epidermis, sebaceous gland and hair follicle. These cells are responsible for regeneration of the hair follicle during hair cycling. Subtraction hybridization experiments have been performed to compare the adult epithelial stem cells of the hair follicle bulge to the non-stem cell compartment. One unique sequence, which has homology to a vitamin D regulated protein, has been selected for further investigation. This transcript has been confirmed to be over-expressed in the stem cell by real-time PCR and immunofluorescence. We are currently characterizing the biochemical properties and functional significance of this unique protein within stem cells, using a retroviral and adenoviral transfection approach.
Molecular Pathogenesis of Tumors from Stem Cells
One of our main goals to understand fate determination of adult epithelial stem cells and alterations in stem cells which lead to tumor formation. Characterizing normal and abnormal pathways of stem cell growth and differentiation is critical for understanding the cellular basis for oncogenesis and for the development of novel approaches to cancer prevention, detection, diagnosis and therapy. The major hypothesis that will be tested in this proposal is that alterations in stem cell fate and growth play a role in tumorigenesis. Epithelial stem cells have a life-span at least as long as that of the organism, and thus they are thought to be susceptible to multiple genetic “hits” which cumulatively may result in tumor formation. In hereditary cancers, one somatic mutation is inherited, leading to increased frequency of two hits and tumor formation. One example is the Muir-Torre syndrome, a familial association of cutaneous sebaceous neoplasia with internal malignancy (mostly colon cancer), caused by mismatch repair defects and microsatellite instability (MSI). We previously showed that human sebaceous skin tumors, both sporadic and from Muir-Torre patients, had a similar immunophenotype to experimentally derived mouse tumors carrying the DNLef1 transgene (Niemann et al, 2003). Since Lef/Tcf genes can be targets of MSI in colon cancers, we hypothesize that Lef/Tcf mutations are also involved the pathogenesis of human sebaceous tumors, analogous to the transgenic mouse. Because earlier work also implicated the hedgehog signaling pathway in sebaceous tumors, we will more closely examine molecular changes in this and other oncogenic pathways. Based on our earlier identification of epithelial stem cells in human skin (Lyle et al, 1998), we have developed methods to isolate and culture these cells, which maintain stem cell properties in vitro. We will now utilize these cells to examine the significance of Lef/Tcf mutations in modifying growth and fate determination of adult epithelial stem cells.
Rotation projects are designed to expose students to the biology of adult stem cells, the mechanisms of tumorigenesis and to provide them with an appreciation for translational cancer research. These projects are focused on the major themes of the lab, which are:
1. Understanding the relative effects of oncogenic mutations on stem cells compared to the non-stem cell population from adult human skin. A key component of this project is to evaluate the Beta-catenin/Lef-1 signaling pathway on cultured epithelial stem cells and non-stem cells.
2. Studying the function of differently expressed genes in mediating stem cell behavior. The goal of this project is to understand the molecular mechanisms which control the critical properties of stem cell self-renewal, proliferation, adhesion and migration.
3. Identifying, isolating and characterizing “cancer stem cells” from human and mouse model tumors. Cancers are thought to possess a sub-population of slowly-cycling cancer stem cells which are responsible for tumor growth, recurrence and metastasis. The goal of this project is to begin to characterize these cells to help better target them therapeutically.
The goal for all of these projects is to use the data obtained to help understand human tumorigenesis at the molecular, cellular and tissue levels, and be able to devise better treatments.