Programmed Cell Death and Translational Medicine
Our laboratory research focuses on the fundamental mechanisms of apoptosis, or programmed cell death. Apoptosis is required for normal tissue development and cellular homeostasis. Deregulation of most growth-promoting factors trigger apoptosis in a “normal cell” and this fundamental characteristic is lost in cancer cells. Our lab has identified the dominant role of a class of anti-cell death proteins called Inhibitor of Apoptosis Proteins (IAP) in cancer cell survival and therapeutic resistance models. The IAPs function by directly inhibiting specific caspases, the key enzymes responsible for execution of cell death. We and others have observed IAP overexpression in many cancer types, and documented that cancer cells are fundamentally dependent on continued high levels of IAP expression.
1. Cellular Stress Response in Tumor Progression and Drug Resistance:
Our studies have identified the critical role of X-linked inhibitor of apoptosis protein (XIAP) considered one of the most potent anti-apoptotic protein in drug resistance by regulating oncogenic signaling through epidermal growth factor receptor pathway (Aird, 2008; 2010). We discovered that cells with XIAP overexpression exhibit a profound suppression of reactive oxygen species (ROS) generation even in the presence of strong ROS/oxidative stress inducers like chemotherapy, radiation and even acute exposure to hydrogen peroxide. This caused a paradoxical activation of downstream proliferative signaling and antioxidant activity in the tumor cells despite targeted inhibition of epidermal growth factor/HER2 receptor activity [Aird et al., Breast Cancer Res Treat. 2012;132(1):109-19]. Studies are ongoing to understand the mechanism of stress response in oncogenic signaling and progression of the cancer cells to a more aggressive, drug tolerant phenotype.
2. Tumor cell signaling-induced immune suppression:
Our laboratory is looking in to the critical question- “How does a tumor cell escape immune control?” Using models of breast, colorectal and pancreatic cells, we are also evaluating mechanisms in tumor cell signaling that lead to immunotherapy resistance. The lab has creatively modified RNA-based agents that can be delivered with high specificity and low toxicity in to a subset of immune cells and act as an adjuvant when targeted T-suppressor cell function [Morse et al., Cancer Gene Ther. 2012;19(1):30-7]. This research was recognized in the Era of Hope Investigator highlight video.
3. Environmental Exposure in Cancer Progression:
Recent studies in our lab have led to development of novel approaches to evaluate the role of environmental chemical-induced adaptive stress response in cells. This includes active collaborations with investigators at EPA, NCCU, and Nicholas School of Environment regarding use of Tox Cast library, Superfund extracts, and datasets. Further, my laboratory has optimized high content, high throughput cell based assays for chemical screening [Sauer SJ, Abstracts].