Project 2

项目2

基本信息

批准号：
10171100
负责人：
Gina Marie DeNicola
金额：
$ 35.43万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-25 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10171100
关键词：
Alveolar Cancer cell line Catalysis Cell Culture Techniques Cell Death Cell Proliferation Cell Survival Cells Cessation of life Consumption Culture Media Cyst Cystathionine Cysteine Cysteine Metabolism Pathway Cystine Dependence Diet Dipeptides Energy Transfer Environment Enzymes Epithelial Cells Exhibits Genotype Glutamates Glutathione Glycine Goals Immune Impairment KRASG12D Liquid substance Lung Lung Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolism Mus Non-Small-Cell Lung Carcinoma Oxidation-Reduction Play Population Primary carcinoma of the liver cells Proteins Resistance Role Serine Serum Source Starvation Sulfur Testing Therapeutic Intervention Tissues Treatment Efficacy Work base cancer cell deprivation extracellular in vivo interstitial lung cancer cell metabolome neoplastic cell resistance mechanism response therapeutic target transcription factor tumor tumor microenvironment uptake

项目摘要

PROJECT 2 SUMMARY INVESTIGATING CYSTEINE ESSENTIALITY IN LUNG CANCER Cancer cells accumulate significant intracellular cysteine due to increased cystine uptake and loss of homeostatic control. Cysteine-derived molecules are crucial for cancer cell survival and proliferation as a consequence of their sulfur moiety, which facilitates diverse functions, including enzyme catalysis, energy transfer, and redox metabolism. Consistently, we have found that many lung cancer cell lines are highly sensitive to cystine starvation and lack the capacity for de novo cysteine synthesis, suggesting they are dependent on exogenous cystine as a source of cysteine. Importantly, the recently developed cyst(e)inase enzyme depletes extracellular cystine and cysteine efficiently, suggesting it may have therapeutic efficacy against lung cancer. However, intracellular metabolic circuits can modify the cellular response to starvation independent of transsulfuration capacity. Thus, understanding the compensatory mechanisms to cysteine starvation is crucial for efficient therapeutic targeting of cysteine in lung cancer. Importantly, our results suggest the glutathione synthesis machinery, an important target of the NRF2 transcription factor, has a glutathione-independent role to protect cells against cysteine starvation-induced ferroptosis. In addition, the tumor microenvironment has significant levels of alternative sources of cysteine, including glutathione, cystathionine and protein, that are lacking in cell culture and may promote survival in the absence of cystine. The central hypothesis of this proposal is that tissue of origin, metabolic responses to cystine starvation, and alteration in sulfur sources within the tumor microenvironment influence cystine essentiality in lung cancer, thereby leading to targetable metabolic vulnerabilities. We will test this hypothesis in the following specific aims: In Aim 1 we will evaluate the influence of tissue and cell of origin on cysteine metabolism and essentiality. In Aim 2 we will decipher metabolic circuits that dictate responsiveness to cysteine limitation. In Aim 3 we will evaluate cysteine metabolism in the tumor microenvironment. The ultimate goal, and the overall impact, of this project is to characterize key determinants of cysteine metabolism and dependence in lung cancer in order to define opportunities for therapeutic intervention.

项目2摘要研究肺癌中半胱氨酸的必要性癌细胞由于胱氨酸摄取增加而积累明显的细胞内半胱氨酸稳态控制。半胱氨酸衍生的分子对于癌细胞的存活和增殖至关重要其硫部分的结果，促进了各种功能，包括酶催化，能量转移和氧化还原代谢。一致地，我们发现许多肺癌细胞系都高度敏感为胱氨酸饥饿，缺乏从头半胱氨酸合成的能力，表明它们依赖外源性胱氨酸作为半胱氨酸的来源。重要的是，最近开发的囊肿（e）inase酶耗竭细胞外半胱氨酸和半胱氨酸有效，表明它可能针对肺癌具有治疗功效。但是，细胞内代谢回路可以独立于改变细胞对饥饿的反应透明度能力。因此，了解半胱氨酸饥饿的补偿机制至关重要为了有效地治疗肺癌中半胱氨酸的治疗靶向。重要的是，我们的结果表明谷胱甘肽合成机械是NRF2转录因子的重要目标，具有与谷胱甘肽无关的作用保护细胞免受半胱氨酸饥饿诱导的铁铁作用。此外，肿瘤微环境具有大型半胱氨酸的替代来源，包括谷胱甘肽，胱淀粉和蛋白质，是缺乏细胞培养，可能在没有胱氨酸的情况下促进生存。该提议的中心假设是起源组织，对胱氨酸饥饿的代谢反应以及肿瘤内硫源的改变微环境影响胱氨酸在肺癌中的必要性，从而导致可靶向代谢漏洞。我们将在以下具体目的中检验这一假设：在AIM 1中，我们将评估组织和原始细胞对半胱氨酸代谢和本质的影响。在AIM 2中，我们将破译代谢回路，以决定对半胱氨酸限制的反应。在AIM 3中，我们将评估肿瘤微环境中的半胱氨酸代谢。该项目的最终目标和整体影响是表征半胱氨酸的关键决定因素代谢和肺癌的依赖性，以定义治疗干预的机会。