Dissecting the role of redox homeostasis and ferroptosis in lung cancer

项目总结 癌症是一种过度增殖的疾病，肿瘤细胞增加其代谢输出以支持持续 生长，这可能会导致氧化应激增加，从而损害大分子，如脂质。多个Pre- 临床和临床研究现已证明，饮食中的抗氧化剂或常见的癌症突变 激活抗氧化途径可促进肿瘤生长和转移，凸显氧化的重要性 肿瘤发生中的动态平衡。然而，氧化应激在肿瘤中是否累积到细胞死亡的临界点 而这种氧化应激依赖的细胞死亡的体内机制仍然难以捉摸。 越来越多的证据表明，氧化应激可导致膜脂过氧化过度- 相关的脂肪酸，导致膜破裂和随后的非凋亡性细胞死亡形式， 称为铁性下垂。已发现许多细胞内机制调节脂质过氧化和铁性下垂， 而且有大量的文献表明癌细胞对铁下垂高度敏感。 体外培养。此外，还展示了几种传统的癌症治疗方法，如化疗和放射治疗。 通过促进脂质过氧化，诱导铁中毒死亡，有效清除癌细胞。然而， 尽管人们对铁性下垂及其在癌症中的治疗潜力充满热情，但在我们的 本提案将涉及的知识： 1)铁下垂是否发生在肿瘤中，它是肿瘤发生的障碍吗？ 2)常见的癌症突变是否调节氧化代谢以抑制铁下垂？ 以前的研究由于缺乏体内可处理的模型来研究铁下垂而受到限制，但在这项研究中，我们 提出一种新的临床前平台来研究铁性下垂作为肿瘤进展的瓶颈，它可以 也可用于治疗(Aim1)。在这些活体模型的基础上，我们还将确定 癌症突变改变代谢程序以维持肿瘤生长，以及克服铁下垂是否是一种 推动疾病进展的潜在机制(AIM2)。

PROJECT SUMMARY Cancer is a disease of hyperproliferation, and tumor cells increase their metabolic output to support sustained growth, which can lead to increased oxidative stress that damages macromolecules like lipids. Multiple pre- clinical and clinical studies have now demonstrated that dietary antioxidants or common cancer mutations that activate antioxidant pathways can promote tumor growth and metastasis, highlighting the importance of oxidative homeostasis in tumorigenesis. However, whether oxidative stress accumulates to a point of cell death in tumors and the in vivo mechanisms of such oxidative stress-dependent cell death remain elusive. Accumulating evidence indicates that oxidative stress can lead to excessive lipid peroxidation of membrane- associated fatty acids, resulting in membrane rupture and subsequently a non-apoptotic form of cell death, termed ferroptosis. Many intracellular mechanisms have been found to regulate lipid peroxidation and ferroptosis, and there is an emerging body of literature suggesting that cancer cells are highly susceptible to ferroptosis in vitro. In addition, several conventional cancer therapies, such as chemotherapy and radiation, have been shown to effectively eliminate cancer cells by promoting lipid peroxidation and inducing ferroptotic death. However, despite the enthusiasm about ferroptosis and its therapeutic potential in cancer, there are major gaps in our knowledge that will be addressed by this proposal: 1) Does ferroptosis occur in tumors, and is it a barrier to tumorigenesis? 2) Do common cancer mutations regulate oxidative metabolism to suppress ferroptosis? Prior studies have been limited by lack of in vivo tractable models to study ferroptosis, but in this fellowship, we propose a novel preclinical platform to investigate ferroptosis as a bottleneck during tumor progression that can also be exploited therapeutically (Aim1). Building upon these in vivo models, we will also determine how specific cancer mutations rewire metabolic programs to sustain tumor growth and whether overcoming ferroptosis is an underlying mechanism driving disease progression (Aim2).