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Autophagy and Epithelial Cell Fate During Anoikis and 3D Morphogenesis

失巢凋亡和 3D 形态发生过程中的自噬和上皮细胞命运

基本信息

批准号：
7808677
负责人：
Jayanta Debnath
金额：
$ 20.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7808677
关键词：
Address Adhesions Affect American Anoikis Antithymoglobulin Autophagocytosis Biochemical Pathway Biological Biological Assay Biomedical Research Cancerous Carcinoma Catabolic Process Cell Death Cell Survival Cells Data Digestion Distant Epithelial Epithelial Cells Experimental Animal Model Extracellular Matrix Face Funding Grant Heel Human In Vitro Individual Laboratories Lung Capacity Malignant Epithelial Cell Malignant Neoplasms Mammary gland Mediating Metastatic to Modeling Morphogenesis Mus Neoplasm Metastasis Occupations Oncogenic Organ Postdoctoral Fellow Process Proliferating Publishing Qualifying RNA Interference Recovery Research Role Seeds Site Source Staging Stress Testing Tissues Validation Wages anticancer research cancer cell cancer therapy fitness follow-up in vivo in vivo Model inhibition of autophagy killings metastatic process neoplastic cell novel parent grant public health relevance tumor tumor progression

项目摘要

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.

描述(由申请人提供)：父母资助测试假设，即当肿瘤细胞失去黏附依赖的细胞外基质(ECM)接触时，自噬或细胞自我消化是肿瘤细胞生存和扩张所必需的。在这里，我们将扩大我们最初拨款的范围，利用体内模型来测试自噬抑制会损害癌细胞在远处器官部位扩散和定植的能力这一假设。以下原因科学地推动了这次修订。首先，上皮癌(癌)的致命性主要归因于肿瘤细胞在全身的不受控制的侵袭和转移。其次，为了转移，癌细胞必须获得在没有适当的ECM接触的情况下存活的病理能力，并随后适应不利的微环境并在远处的器官部位定居。面对这些压力，肿瘤细胞究竟是如何适应并茁壮成长的，在很大程度上仍不清楚。我们最近发现，在没有黏附的情况下，自噬促进了上皮细胞的存活。作为我们父母资助的一部分正在进行的研究表明，自噬在被剥夺了ECM接触的癌细胞中被强有力地诱导；此外，当自噬被抑制时，这些致癌细胞不会在锚定独立的条件下生长和增殖。这一体外积累的数据有力地表明，自噬促进了肿瘤细胞向转移部位的扩散，但这一假设需要在体内进行验证。因此，我们将扩大我们最初拨款的范围，并测试抑制自噬是否会损害癌细胞在远处器官部位扩散和定居的能力。通过这个额外的目标，我们将获得关于自噬如何促进肿瘤细胞在扩散和转移过程中的存活和细胞适合性的独特信息。与公共卫生相关：源于上皮组织的癌症，称为癌，是非常常见和致命的人类肿瘤。这些癌症如此致命的一个重要原因是肿瘤细胞在全身扩散和转移。我们提出的研究将是第一次测试自噬，一种基本的细胞自我消化过程，是否可以靶向阻止癌细胞的扩散和转移。