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

摘要 癌症的特点是细胞代谢的改变促进了肿瘤的发生，然而我们的 了解这些代谢变化是如何发生的，以及它们是如何机械地支持癌细胞的 功能仍然缺乏。虽然一些代谢变化可重复地作为致癌的直接结果而发生 突变，随着时间的推移，其他代谢变化通过适应性代谢蛋白表达的变化发生 使细胞能够克服癌症进展过程中的代谢缺陷。值得注意的是，后一组是 被预测为功能上重要的代谢变化的富集物，表明它们的鉴定将 与癌症研究特别相关。然而，详细了解哪些新陈代谢 变化是适应的结果，由于缺乏直接研究可重复性的模型而受到阻碍 癌症中的代谢适应。此外，基于种族的癌症相关适应差异的数据 也没有造成健康差距的种族因素。在这里，我们建议解决这一知识鸿沟 通过研究我们最近建立的代谢适应系统的机制，其中损失 肿瘤抑制因子琥珀酸脱氢酶(SDH)功能突变的选择 线粒体电子传递链复合体I组分的整合表达，最终 支持细胞新陈代谢和细胞增殖。使用这个系统，我们将研究代谢驱动因素 在SDH缺陷细胞中的复杂I适应(目标1)和使用基因表达的多组学测量 过程，如表观遗传学、转录和蛋白平衡，以确定执行的细胞过程 对复合体I表达的适应性改变(目标2)。我们还将采取系统的方法，使用最新情况- 利用包含多体测量的公开可用患者肿瘤数据集的ART统计方法 和患者元数据，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)。这一多学科全面项目还涉及该伙伴关系的指导原则 (见总体部分)，对不同的研究团队进行包容性指导，并将研究成果传播到 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.