Rheinwald Lab

The long-term research interest of the Rheinwald laboratory is to understand the mechanisms that regulate growth, differentiation, and malignant transformation of epithelial cells. We currently are investigating cell senescence and immortalization, wound healing, and neoplastic progression. Our major focus is the keratinocyte—the cell type that forms stratified squamous epithelia such as the oral, corneal, conjunctival, and exocervical epithelia, and the epidermis. We also study other epithelial cell types, including the mesothelial cell, which covers all surfaces within the peritoneal, pleural, and pericardial cavities and is the precursor form of the asbestos-induced cancer called mesothelioma. Our projects employ retroviral and lentiviral vectors to stably express specific oncogenes and other growth regulatory genes or RNAi’s targeting specific tumor suppressor genes in primary human cells so that we can use genetic approaches to investigate complex regulatory and pathologic mechanisms. Other experimental tools we use include organotypic culture, immunostaining, Western blotting, time-lapse photography, flow cytometry, DNA microarray analysis of gene expression, and real-time PCR.

Our lab is currently devoting most of its effort to understanding cell aging and senescence in epithelial cells and how cells evade these processes during neoplastic progression. Keratinocyte senescence arrest in culture is enforced by induction of the cell cycle inhibitor p16^INK4A. We identified the point during neoplastic progression to squamous cell carcinoma at which p16 becomes expressed in vivo to function as a tumor suppressor. This induction of p16 occurs coordinately with expression of large amounts of the extracellular adhesion protein Laminin 5 in cells that are just beginning to invade, in a process that has proved to resemble the normal keratinocyte wound healing response, including cellular hypermotility. We are working on projects aimed at understanding the signal pathways that trigger the p16/Laminin 5 response both in normal wound healing and in early invasive cancer.

We also are investigating growth regulatory mechanisms that become disabled or bypassed during neoplastic progression of mesothelial cells to mesothelioma, including those responsible for oxidative stress-induced growth arrest and for dependence upon an exogenous source of polypeptide mitogens.

Recently we have begun to investigate the potential of human embryonic stem cells to undergo differentiation into keratinocyte and other somatic epithelial lineages in culture.

In addition to our research activities, the Rheinwald lab also serves as a Cell Culture Core laboratory, providing human cell lines and culture methods to academic investigators. These Core services are supported by Brigham and Women’s Hospital, a Skin Disease Research Center grant from NIH, and by fees charged to users.