Fred Hutchinson Cancer Center
Graduate Group: Cell and Molecular Biology
Thesis Topic: Hypoxia Inducible Factors Regulate the p53 and Noth Pathways to Promote Cancer
After graduation, Jessica moved to Seattle where her husband has accepted a human anesthesiologist position. She wanted to pursue a post-doc in cancer biology after taking a little time with their newborn baby. As of April 2011, Jessica accepted a postdoctoral position at the Fred Hutchinson Cancer Center in Dr. Jason Biela's laboratory.
Jessica’s thesis focused on the role of Hypoxia Inducible Factors (HIF1alpha and HIF2alpha) in tumorigenesis and tumor responses to radiation therapy. Hypoxia Inducible Factors (HIFs) are alpha-beta heterodimeric transcription factors that regulate important cellular processes, allowing both normal and cancerous cells to adapt to low oxygen conditions. Two central HIFalpha subunits, HIF1alpha and HIF2alpha, are highly expressed in many tumors and are correlated with poor patient prognosis. Jessica sought to further characterize their roles in cancer therapy responses and in tumorigenesis. While HIF1alpha promotes p53-dependent cell death in tumor cells, HIF2alpha has been suggested to regulate a subset of antioxidant enzymes, leading us to hypothesize that HIF2alpha may protect cells against Reactive Oxygen Species (ROS)-dependent damaging agents such as radiation. She demonstrated that HIF2alpha inhibits the p53 pathway both in vitro and in Renal Clear Cell Carcinoma (ccRCC) patient samples, by limiting the amount of DNA damage incurred by the cell. HIF2alpha’s protective effect stems from its ability to maintain cellular redox balance, in the absence of which intracellular ROS increase and cells become much more sensitive to damage. Moreover, a novel p53 mutant mouse model suggested a role for HIF1alpha-mediated Notch stabilization in tumorigenesis. Indeed, HIF1alpha heterozygosity led to a significant reduction in the incidence of thymic lymphomas strongly associated with impaired Notch pathway activity. Both studies elucidated mechanisms whereby the HIFalpha subunits impact directly on tumor biology and provided evidence in support of the development of specific HIF inhibitors for use in cancer therapy.