Principal Investigator - Jayanta Debnath
The lethality of breast cancers is primarily because tumor cells are able to invade, disseminate and form metastases throughout the body. By identifying the pathways used by tumor cells to survive adverse stresses and to invade surrounding tissue, we may develop innovative strategies to prevent metastasis. We propose that an important therapeutic target is a fundamental cellular stress response pathway, called autophagy, because it promotes both tumor cells survival and invasion. Autophagy is literally the process of “self-eating” in which cells digest small bits and pieces of themselves and recycle the resulting nutrients in order to survive starvation or stress. Although previous work from our lab as well as others demonstrates that autophagy functions as a survival pathway in cancer, we have recently uncovered a new function for autophagy—promoting breast cancer cell invasion. Inhibiting autophagy profoundly diminishes the ability of breast cancer cells to invade the surrounding tissue and reduces metastasis in vivo. In further work, we have discovered that these defects in invasion and metastasis in autophagy-defective cells are due to the impaired secretion of multiple factors needed for invasion. Overall, our findings reveal an unexpected role for autophagy in facilitating secretion during tumor cell invasion. Accordingly, we propose that by inhibiting autophagy, we will not only predispose breast cancer cells to undergo cell death when exposed to stress, but more importantly, we will impede their ability to secrete the factors critical for invasion and dissemination to foreign sites, thereby impeding breast cancer progression to metastasis. We will utilize both in vitro and in vivo approaches in breast cancer models to test this fundamental new concept in the field. From a therapeutic standpoint, our long-term objective is to determine whether and how autophagy can be most effectively targeted as “an Achilles heel” to prevent breast cancer progression.