Molecular Pathogenesis of Tumors from Stem Cells
Stephen Lyle, MD, PhD
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:
Do cancers arise from adult stem cells, and if so, what are the molecular mechanisms which transform a stem cell?
Do cancers themselves have stem cells, termed “cancer stem cells”, which are responsible for tumor growth, recurrence and metastasis?
Current Research Projects in the Lyle Laboratory
National Institutes of Health – National Cancer Institute
- R01CA118916: LEF/TCF Function in Adult Stem Cell Fate and Tumorigenesis
The long-term objectives of this proposal are to understand how specific genetic changes cause abnormal fate determination and growth regulation within adult epithelial stem cells and how these changes promotw tumor formation from stem cells. The specific aims are; 1.) Determine the cellular mechanisms by which dysregulated LEF-1 promotes tumorigenesis in multi-potent stem cells of human skin; 2.) Determine the cellular and molecular properties of a new sebaceous tumor cell line showing deficient LEF-1 signaling; 3.) Survey the spectrum and incidence of LEF/TCF mutations in human sebaceous skin tumors and correlate with tumor morphology. In order to accomplish these aims, we will use a novel system to isolate adult epithelial stem cells of human skin and study the cellular changes induced by altered LEF-1 signaling. We will use in vitro assays, as well as molecular and biochemical tests to characterize a new sebacaous tumor cell line. Lastly, a large archival tissue bank of sebaceous tumors will be screened by several molecular techniques to identify mutations within the LEF-1, TCF-3, and TCF-4 genes.
W.M. Keck Foundation
The foundation for the studies described n this proposal is the identification of centrolin, a novel protein localized to the centriolin, a novel protein localized to the centrosome and midbody (MB), structures essential for cell division. In human cultured cells centriolin functions in an under explored area of cell division called abscission, where the cell splits to create the two new daughter cells. We discovered a series of asymmetric events during abscission that produced daughter cells withdifferent properties, organelles, fates, and lifespans. These observations change the wat we view the fundamental process of cell division in that daughter cells are not created equal, but are born different.