Autophagy and Epithelial Cell Fate During Anoikis and 3D Morphogenesis

描述（由申请人提供）：在癌症进展过程中，肿瘤细胞在缺乏适当的细胞外基质（ECM）接触的情况下获得生存和扩张的能力，这有利于早期癌症的形成和后期的传播和转移。整合素介导的细胞粘附到ECM是正常上皮细胞存活的关键；事实上，ecm剥夺的正常细胞（与癌细胞不同）会发生凋亡，称为anoikis。组成型生长因子通路激活是癌细胞逃避疾病的一种常见机制。激活关键生长因子信号的癌基因，如Ras/MAPK和PI3K/Akt通路，保护癌细胞免于死亡。然而，我们最近发现了另一种机制在嗜酸自噬过程中保护上皮细胞。自噬是一种严格调节的自我消化过程，在饥饿和压力下促进细胞存活。有趣的是，在后续研究中，我们发现在表达激活PI3K/Akt或Ras/MAPK的癌基因的分离细胞中，自噬被强烈诱导。基于这些发现，我们假设当失去粘附依赖的ECM接触时，自噬是致癌细胞存活所必需的。我们将通过三个具体目标来检验这一假设。在Aim 1中，我们将确定癌基因如何调节分离诱导的自噬，以及自噬是否促进癌基因表达细胞在anoikis和3D形态发生过程中的存活。在Aim 2中，我们将识别ECM脱离诱导自噬的信号。在Aim 3中，我们将定义癌细胞在致瘤转化和不依赖粘附存活过程中自噬的促瘤与抑制作用。由于自噬是由一组明确的基因（称为ATGs）调节的，不同于已建立的细胞凋亡调节因子，我们的研究可能揭示独特的机制和途径来开发对抗人类癌症。公共卫生相关性：我们最近发现自噬是细胞脱离细胞外基质的一种新的生存机制，是肿瘤细胞在癌症进展和转移过程中面临的主要压力。自噬是细胞在压力下消化自身内容物（字面意思是“吃掉自己”）的基本过程。随着对控制自噬治疗癌症的兴趣迅速增强，我们提出的研究将提供独特和及时的见解，了解如何利用自噬来杀死或抑制癌细胞从细胞外基质分离的扩张，从而阻碍进展和转移。

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.