The Role of Metabolic Alterations in Anchorage-Independent Survival

描述（由申请人提供）：癌细胞在缺乏正常基质的情况下存活的能力对于肿瘤进展和转移至关重要。从细胞外基质（ECM）分离的正常（非致瘤性）细胞经历半胱天冬酶依赖性死亡（称为失巢凋亡），这是癌细胞中经常有缺陷的现象，从而有助于肿瘤进展。有趣的是，最近的研究表明，抑制失巢凋亡不足以使细胞在异常基质环境中存活，因为分离的细胞可以通过替代死亡途径死亡。我们实验室的初步工作和其他小组的相关研究表明，细胞代谢的改变可能是在缺乏正常基质的情况下诱导这种替代性死亡途径的基础，并且癌基因可以调节细胞代谢以防止非凋亡性死亡。因此，调节细胞代谢以诱导肿瘤细胞中的非凋亡性细胞死亡可能是有用且重要的化疗策略。因此，我们提出以下具体目标，以解决锚定非依赖性生存代谢变化的作用。I.分析从细胞外基质脱离的细胞中低代谢活性的基础。二.了解癌基因如何挽救从细胞外基质分离的细胞中的代谢缺陷。三.描述癌基因介导的代谢修饰对肿瘤进展的重要性。癌细胞与正常细胞的许多区别之一是当它们迁移到不适当的环境时，它们不能进行“细胞自杀”（称为凋亡）。最近，人们发现癌细胞还必须避免另一种形式的细胞死亡（与凋亡不同），以便在正常环境之外生存，这种死亡似乎取决于癌细胞处理营养物质的方式。因此，了解癌细胞如何在其正常环境之外处理营养物质将提供有价值的信息，这些信息可以确定通过诱导这种替代形式的细胞死亡来杀死不适当地离开其环境的癌细胞的新方法。

DESCRIPTION (provided by applicant): The ability of cancer cells to survive in the absence of normal matrix is critical for tumor progression and metastasis. Normal (non-tumorigenic) cells that detach from the extracellular matrix (ECM) undergo caspase-dependent death (known as anoikis), a phenomenon that is frequently defective in cancer cells, thereby contributing to tumor progression. Interestingly, recent studies have revealed that inhibiting anoikis is not sufficient to allow for cell survival in abnormal matrix environments, as detached cells can die by an alternative death pathway. Preliminary work from our laboratory and correlative studies by other groups suggest that alterations in cellular metabolism may underlie the induction of this alternative death pathway in the absence of normal matrix and that oncogenes can modulate cellular metabolism to protect from non- apoptotic death. Thus, the modulation of cellular metabolism to induce non-apoptotic cell death in tumor cells may be a useful and important chemotherapeutic strategy. Therefore, we propose the following specific aims to address the role of metabolic changes in anchorage-independent survival. I. To analyze the basis for low metabolic activity in cells that have detached from the extracellular matrix. II. To understand how oncogenes rescue metabolic defects in cells that detach from the extracellular matrix. III. To characterize the importance of oncogene-mediated modifications in metabolism on tumor progression. Relevance One of the many things that differentiates cancer cells from normal cells is their inability to commit "cellular suicide" (known as apoptosis) when they migrate to an inappropriate environment. Recently, it has been discovered that cancer cells must also avoid an alternative form of cell death (distinct from apoptosis) in order to survive outside of their normal environment, and this death seems to be dependent on the way cancer cells process nutrients. Therefore, an understanding of how cancer cells process nutrients outside of their normal environment will provide valuable information that may identify novel ways to kill cancer cells that have inappropriately left their environments through the induction of this alternative form of cell death.