The Role of Metabolic Alterations in Anchorage-Independent Survival

描述（由申请人提供）：癌细胞在没有正常基质的情况下存活的能力对肿瘤的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caspase依赖性死亡（称为anoikis），这种现象在癌细胞中经常存在缺陷，从而促进肿瘤进展。有趣的是，最近的研究表明，抑制anoikis并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另一种死亡途径死亡。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死亡途径的基础，癌基因可以调节细胞代谢以保护非凋亡性死亡。因此，调节细胞代谢诱导肿瘤细胞的非凋亡性细胞死亡可能是一种有用和重要的化疗策略。因此，我们提出以下具体目标来解决代谢变化在非锚定生存中的作用。1 .分析从细胞外基质分离的细胞代谢活性低的基础。2。了解癌基因如何拯救脱离细胞外基质的细胞中的代谢缺陷。3。表征肿瘤进展中肿瘤基因介导的代谢修饰的重要性。癌细胞与正常细胞的区别之一是，当癌细胞迁移到不合适的环境时，它们无法进行“细胞自杀”（称为凋亡）。最近，人们发现癌细胞也必须避免另一种形式的细胞死亡（不同于细胞凋亡），以便在正常环境之外生存，这种死亡似乎依赖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外处理营养物质将提供有价值的信息，可能会找到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.