My career began with the identification of cell surface markers on invasive cells, and led to the discovery of how integrins ?v?3 and ?v?5 on endothelial cells respond to cues within the tumor microenvironment to promote angiogenesis. I later demonstrated that ?V integrins on tumor cells use these same fundamental pathways to achieve aggressive, invasive, and metastatic behavior. Now, my R35 proposal represents a further evolution of these concepts to ask how tumor cells undergo reprogramming in response to cellular stresses, including hypoxia, nutrient deprivation, or cancer therapy. We find that ?v?3 expression can be induced by stress to reprogram tumor cells toward a stress-tolerant, drug-resistant, stem-like state that is associated with tumor progression and metastasis for a wide range of cancers. Because individual tumors use this integrin to overcome unique challenges, we will define how ?v?3 activates downstream effectors that vary between tumor type, genetic profile, and microenvironment. The overall goal of my future research program is to understand how such tumors use integrin ?v?3 to gain stress tolerance so that we can devise ways to attack this process therapeutically. This proposed research will not only lead to a fundamental understanding of how tumors adapt to therapy or microenvironmental stress, but it should identify new druggable targets to limit cancer progression by preventing or overcoming tumor cell drug resistance and stress tolerance.
My research has focused on the overarching theme of how cell surface receptors mediate an invasive phenotype by promoting adaptations that support cell survival in the face of stress. While this is a critical component of physiological remodeling processes such as angiogenesis, tumor cells often hijack these same pathways to promote metastasis and tumor progression. Throughout my career, I have emphasized the combination of basic and translational cancer research which has resulted in one cancer drug recently approved by the FDA and a second drug that has successfully completed Phase III trials.