Thea Tlsty, PhD


Our laboratory is interested in the earliest events that cause cancer formation in human cells. We use genetic, molecular, biochemical, and cytogenetic techniques to study the cell biology of tumor cell formation and progression in human tissue. An important aspect of these events includes the regulation of genomic instability. These studies have led us to the investigation of signal transduction pathways that govern a cell's response to environmental cues as well as the origin of tumor-facilitating signals provided by the microenvironment.

Initial studies demonstrated that gene amplification, one type of genomic instability, could be detected in tumor cells, but not in normal cells. We identified the first set of genes that controls this process in human cells. The tumor suppressor gene, p53, prevents gene amplification in primary cells, essentially by acting as part of a signal transduction pathway that senses genomic damage and allows for the cell to halt cell cycle progression to increase chances for repair. Knowledge of these response processes can be used in the diagnosis of cancer or the identification of individuals that are predisposed to cancer. We have begun screening studies to identify such individuals. Furthermore, genomic instability is known to underlie the processes of metastasis and the generation of drug-resistant tumor cells, two events that impair cancer treatment. We would like to understand how these processes are modulated in human cells so that it can be used to increase therapeutic efficiency.

While studying the modulation of genetic integrity in the transforming cell we found that signals from the stroma, specifically the fibroblasts associated with the cancer lesion, could facilitate tumor formation. This has become an active area of investigation and our laboratory is identifying the molecular dialog that stimulates tumor formation and targets for its prevention.

More recently, we have identified a subpopulation of human mammary epithelial cells that exhibit striking pre-malignant phenotypes and stem cell characteristics. Cells lacking p16 activity acquire stem cell characteristics and can bypass senescent signals. We are extending our studies to determine how these cells contribute to the carcinogenic processes and how they can be reprogrammed or selectively eliminated.