Autophagy and Epithelial Cell Fate During Anoikis and 3D Morphogenesis

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DESCRIPTION (provided by applicant): During carcinoma progression, tumor cells acquire the ability to survive and expand in absence of proper extracellular matrix (ECM) contact, which facilitates both early carcinoma formation and the later stages of dissemination and metastasis. Integrin-mediated cell adhesion to ECM is critical for normal epithelial cell survival; in fact, ECM-deprived normal cells (unlike cancer cells) undergo apoptosis, termed anoikis. Constitutive growth factor pathway activation is a common mechanism utilized by cancer cells to evade anoikis. Oncogenes that activate key growth factor signals, such as the Ras/MAPK and PI3K/Akt pathways, protect cancer cells from death. However, we recently discovered that another mechanism protects epithelial cells during anoikis-autophagy. Autophagy is a tightly regulated self-digestion process that promotes cell survival during starvation and stress. Interestingly, in follow-up studies, we have found that autophagy is robustly induced in detached cells expressing oncogenes that activate either PI3K/Akt or Ras/MAPK. Based on these findings, we hypothesize that autophagy is required for oncogenic cells survival when deprived of adhesion dependent ECM contact. We will test this hypothesis through three specific aims. In Aim 1, we will determine how oncogenes regulate detachment-induced autophagy and whether autophagy promotes the survival of oncogene-expressing cells during anoikis and 3D morphogenesis. In Aim 2, we will identify the signals through which ECM detachment induces autophagy. In Aim 3, we will define the tumor promoting vs. suppressive functions of autophagy in cancer cells during oncogenic transformation and adhesion independent survival. Since autophagy is regulated by a defined set of genes (called ATGs), distinct from established apoptosis regulators, our studies may reveal unique mechanisms and pathways to exploit against human carcinomas. PUBLIC HEALTH RELEVANCE: We recently discovered that autophagy is a novel survival mechanism for cells detached from extracellular matrix, a major stress faced by tumor cells during cancer progression and metastasis. Autophagy is a fundamental process in which a cell digests its own contents (i.e. literally "eats itself") during times of stress. As interest in manipulating autophagy to treat cancer rapidly intensifies, our proposed studies will provide unique and timely insight into how autophagy can be exploited to kill or suppress the expansion of cancer cells detached from extracellular matrix, and thus, impede progression and metastasis.