Autophagy and Epithelial Cell Fate During Anoikis and 3D Morphogenesis

描述（由申请人提供）：父母资助测试假设自噬，或细胞自我消化，是肿瘤细胞生存和扩张所必需的，当被剥夺粘附依赖的细胞外基质（ECM）接触时。在这里，我们将扩大我们最初的资助范围，利用体内模型来验证自噬抑制损害癌细胞在远处器官部位传播和定植的能力的假设。以下原因科学地推动了这一修订。首先，上皮性癌症（癌）的致命性主要归因于肿瘤细胞在全身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植。肿瘤细胞在面对这些压力时究竟是如何适应和茁壮成长的，这在很大程度上仍不清楚。我们最近发现，自噬促进上皮细胞在没有粘附的情况下存活。作为母公司资助的一部分，正在进行的研究表明，在失去ECM接触的癌细胞中，自噬被强烈诱导；此外，当自噬被抑制时，这些致癌细胞在锚定独立的条件下不会生长和增殖。这些累积的体外数据强烈表明，自噬促进了肿瘤细胞向转移部位的传播，但这一假设需要在体内验证。因此，我们将扩大我们最初的资助范围，并测试自噬抑制是否会损害癌细胞在远处器官部位扩散和定植的能力。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传播和转移过程中的存活和细胞适应性的独特信息。

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.