Project 2

项目2总结 探讨半胱氨酸在肺癌中的重要性 癌细胞由于摄取半胱氨酸的增加和半胱氨酸的丢失，在细胞内积累了大量的半胱氨酸 动态平衡控制。半胱氨酸衍生的分子对于癌细胞的生存和增殖至关重要 硫磺部分的结果，这促进了各种功能，包括酶催化，能量 转移和氧化还原代谢。我们一致地发现，许多肺癌细胞系对此高度敏感。 对半胱氨酸饥饿和缺乏从头合成半胱氨酸的能力，这表明它们依赖于 作为半胱氨酸来源的外源半胱氨酸。重要的是，最近开发的胞囊(E)酶耗尽。 胞外半胱氨酸和半胱氨酸有效，提示其可能对肺癌有治疗作用。 然而，细胞内代谢回路可以改变细胞对饥饿的反应，不依赖于 转硫量。因此，了解半胱氨酸饥饿的补偿机制是至关重要的。 用于半胱氨酸在肺癌中的有效靶向治疗。重要的是，我们的结果表明谷胱甘肽 合成机制是NRF2转录因子的一个重要靶点，对谷胱甘肽不依赖于谷胱甘肽的作用。 保护细胞免受半胱氨酸饥饿引起的铁下垂。此外，肿瘤微环境已经 大量的半胱氨酸替代来源，包括谷胱甘肽、半胱硫氨酸和蛋白质，这些都是 缺乏细胞培养，在没有胱氨酸的情况下可能会促进存活。这项提议的核心假设是 是组织起源，对胱氨酸饥饿的代谢反应，以及肿瘤内硫源的变化 微环境影响肺癌中胱氨酸的重要性，从而导致靶向代谢 漏洞。我们将在以下具体目标中检验这一假设： 在目标1中，我们将评估组织和细胞来源对半胱氨酸代谢的影响和必要性。 在目标2中，我们将破译决定对半胱氨酸限制反应的代谢回路。 在目标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总体影响是确定半胱氨酸的关键决定因素。 肺癌的新陈代谢和依赖性，以确定治疗干预的机会。

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.