The Department of Biological Sciences at the University of Notre Dame is pleased to present a seminar by Dr. Mary Helen Barcellos-Hoff, Professor in the Departments of Radiation Oncology and Cell Biology at NYU Langone Medical Center. The seminar will take place on Monday, December 16 at 4pm in 283 Galvin Life Science.
The goal of Dr. Barcellos-Hoff's research is to understand how tissues integrate information across multiple scales of organization and to use this information in modeling critical events in carcinogenesis. Her lab studies ionizing radiation (IR), a prototypic carcinogen, in terms of its effects on cell phenotype and tissue interactions. Identifying when and how tissue alterations contribute to the action of IR may provide a means to inhibiting its carcinogenic potential, as well as a better understanding of how normal tissues suppress carcinogenesis. A major focus of her laboratory is to study the multiple and complex mechanisms by which transforming growth factor beta (TGFb) affects irradiated cells and tissues. The combined effects of TGFb and IR have profound effects on epithelial phenotype, centrosome regulation and genomic stability. They discovered that TGFb is activated in response to IR, which in turn revealed that TGFb is essential for epithelial cells to mount the canonical DNA damage response as shown by the failure of Tgfb1 null murine epithelial cells to undergo cell cycle arrest or apoptosis in response to irradiation. They showed that the abrogated DNA damage response is due to regulation of ATM kinase activity and can be phenocopied using small molecule TGFb inhibitors in human epithelial cells. The requirement for TGFb in the genotoxic stress program also provides a previously unsuspected avenue to modulate radiotherapy. Pharmaceutical means to inhibit TGFb are in clinical trials. They have translated their discovery that TGFb ensures effective response to DNA damage by testing TGFI? inhibitors in preclinical human and mouse models of breast, brain and lung cancer. TGFb inhibition in conjunction with radiotherapy increases sensitivity to clonogenic death and tumor growth delay. A direct and specific requirement for TGFb in the genotoxic stress program provides an important vital link between cell fate and tissue integrity and underscores the dynamic interaction between target cells and other cell types. They developed a radiation chimera model to test this idea. In this model the mice are irradiated, then transplanted with unirradiated oncogenically primed mammary epithelial cells. Radiation accelerated tumorigenesis but surprisingly also affects the type of tumor, promoting those that are more aggressive basal-like phenotype. This model offers novel insight into the carcinogenic process.
Originally published at biology.nd.edu.