Project 2: Systemic Understanding of Cellular Mechanisms of Metabolic Adaptations in Cancer

摘要 癌症的特征在于细胞代谢的改变，其促进肿瘤发生，然而我们的研究发现， 了解这些代谢变化是如何发生的，以及它们如何在机械上支持癌细胞 功能仍然缺乏。虽然一些代谢变化可重复地发生，作为致癌的直接结果， 随着时间的推移，其他代谢改变通过适应性代谢蛋白表达变化而发生。 让细胞克服癌症发展过程中的代谢缺陷。值得注意的是，后一组是 预测富含功能重要的代谢变化，这表明它们的鉴定将 与癌症研究有着特别的关联。然而，详细了解哪些代谢 由于缺乏直接研究可重复性的模型， 癌症的代谢适应。此外，基于种族的癌症相关适应差异的数据 或种族因素造成的健康差异。在这里，我们建议解决这一知识差距 通过研究我们最近建立的代谢适应系统的机制， 肿瘤抑制因子琥珀酸脱氢酶（SDH）中的功能突变选择具有以下特征的细胞： 线粒体电子传递链复合物I的组分的一致表达，其最终 支持细胞代谢和细胞增殖。使用这个系统，我们将研究代谢驱动因素， 复合物I适应SDH缺陷细胞（目的1），并使用基因表达的多组学测量 过程，如表观遗传学，转录和蛋白质稳态，以确定制定的细胞过程， 适应性改变复杂的I表达（目标2）。我们还将采取系统的方法，利用国家的- 利用公开可用的包含多组测量的患者肿瘤数据集的现有技术统计方法 以及患者元数据，以便识别癌症期间代谢蛋白表达的适应性变化 进展（目标3）。这个多学科的全面项目还涉及伙伴关系的指导原则 (see为不同的研究团队提供包容性的指导，并将研究成果传播给 帮助服务不足的社区，帮助教育和为下一代研究人员提供机会。

ABSTRACT Cancers are characterized by alterations to cellular metabolism that promote tumorigenesis, however our understanding of how these metabolic changes are enacted and how they mechanistically support cancer cell function remains lacking. While some metabolic changes reproducibly occur as a direct result of oncogenic mutations, other metabolic alterations occur over time through adaptive metabolic protein expression changes that allow cells to surmount metabolic deficiencies during cancer progression. Notably, this latter group is predicted to be enriched for functionally important metabolic changes, suggesting that their identification would have particularly relevance for cancer research. However, detailed understanding of which metabolic alterations are the result of adaptations is hampered by the lack of models for directly studying reproducible metabolic adaptations in cancer. Additionally, data on differences in cancer-related adaptations based on race or ethnicity that contribute to health disparities are lacking. Here, we propose to address this knowledge gap by investigating the mechanisms of metabolic adaptation system that we have recently established, where loss of function mutations in the tumor suppressor succinate dehydrogenase (SDH) selects for cells with concordant expression of components of mitochondrial electron transport chain complex I, which ultimately supports cell metabolism and cell proliferation. Using this system, we will investigate the metabolic drivers of complex I adaptations in SDH deficient cells (Aim 1) and use polyomics measurements of gene expression processes, such a epigenetics, transcription, and proteostasis, to identify the cellular processes that enact adaptive changes to complex I expression (Aim 2). We will also take a systematic approach using state-of-the- art statistical methods to leverage publicly available patient tumor datasets containing polyomic measurements and patient metadata in order to identify adaptive changes to metabolic protein expression during cancer progression (Aim 3). This multidisciplinary Full Project also addresses the Partnership’s Guiding Principles (see Overall section) for inclusive mentoring of diverse research teams and for research dissemination to underserved communities, helping to educate and provide opportunities for next generation of researchers.