Autophagy and Epithelial Cell Fate During Anoikis and 3D Morphogenesis

University Of California, San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): The parent grant tests the hypothesis that autophagy, or cellular self-digestion, is required for tumor cell survival and expansion when deprived of adhesion dependent extracellular matrix (ECM) contact. Here, we will expand the scope of our original grant to utilize in vivo models to test the hypothesis that autophagy inhibition compromises the ability of cancerous cells to disseminate and colonize at distant organ sites. The following reasons scientifically motivate this revision. First, the lethality of epithelial cancers (carcinomas) is primarily attributed to the unchecked invasion and metastases of tumor cells throughout the body. Second, in order to metastasize, carcinoma cells must acquire the pathological ability to survive in the absence of proper ECM contact and subsequently, to adapt to untoward microenvironments and colonize at distant organ sites. How tumor cells exactly adapt and thrive in the face of these stresses still remains largely unclear. We recently discovered that autophagy promotes epithelial cell survival in the absence of adhesion. Ongoing studies performed as part of our parent grant demonstrate that autophagy is robustly induced in cancerous cells deprived of ECM contact;furthermore, when autophagy is inhibited, these oncogenic cells do not grow and proliferate in anchorage independent conditions. This accumulating in vitro data strongly suggests that autophagy facilitates the dissemination of tumor cells to metastatic sites, but this hypothesis requires validation in vivo. Hence, we will expand the scope of our original grant and test if autophagy inhibition will compromise the ability of cancerous cells to disseminate and colonize at distant organ sites. Through this additional aim, we will gain unique information on how autophagy promotes the survival and cellular fitness of tumor cells during dissemination and metastasis. PUBLIC HEALTH RELEVANCE: Cancers arising from epithelial tissues, called carcinomas, are highly common and deadly human tumors. An important reason that these cancers are so lethal is because tumor cells disseminate and metastasize throughout the body. Our proposed studies will be the first to test whether autophagy, a fundamental cellular self-digestion process, can be targeted to block carcinoma cell dissemination and metastasis.