Dissecting the role of redox homeostasis and ferroptosis in lung cancer

剖析氧化还原稳态和铁死亡在肺癌中的作用

基本信息

批准号：
10679946
负责人：
Katherine Wu
金额：
$ 5.27万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-04 至 2026-04-03
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679946
关键词：
Address Antioxidants Automobile Driving Buffers Cancer Etiology Cell Death Cell Death Induction Cell Line Cell Respiration Cell Survival Cellular Membrane Cellular Stress Cessation of life Chemicals Chemotherapy and/or radiation Clinical Clinical Research Coenzyme Q10 Complement Data Development Disease Disease Progression Enzymes Fatty Acids Fellowship Future Genes Genetic Genetic Transcription Genetically Engineered Mouse Glutathione Goals Growth Homeostasis Human Immunotherapy In Vitro Investigation Iron Kinetics Knowledge Lipid Peroxidation Lipid Peroxides Lipids Literature Lung Adenocarcinoma Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Medical Membrane Metabolic Metabolism Modeling Molecular Monitor Mutate Mutation Neoplasm Metastasis Output Oxidation-Reduction Oxidative Stress Pathway interactions Phosphotransferases Play Polyunsaturated Fatty Acids Pre-Clinical Model Predisposition Production Prognosis Proliferating Publishing Reactive Oxygen Species Regulation Reporting Resistance Response Elements Role Rupture STK11 gene Signal Transduction Study models Testing Therapeutic Translating Tumor Burden Tumor Promotion United States Work cancer cell cancer therapy cancer type carcinogenesis chemotherapy conventional therapy cost dietary antioxidant experimental study gain of function genetic manipulation improved in vivo in vivo Model insight interest iron metabolism loss of function lung cancer cell macromolecule metabolomics mouse model mutant neoplastic cell novel oxidation oxidative damage peroxidation pre-clinical preclinical study programs public health relevance response screening sensor tetrahydrobiopterin therapeutic biomarker therapeutic target transcription factor transcriptomics tumor tumor growth tumor progression tumorigenesis

项目摘要

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).

项目概要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的生命活动。生长，这可能导致氧化应激增加，从而损害脂质等大分子。多重预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以促进肿瘤生长和转移，凸显了氧化的重要性肿瘤发生中的稳态。然而，氧化应激是否累积到肿瘤细胞死亡的程度这种氧化应激依赖性细胞死亡的体内机制仍然难以捉摸。越来越多的证据表明，氧化应激可导致细胞膜过度脂质过氧化。相关脂肪酸，导致膜破裂并随后导致非凋亡形式的细胞死亡，称为铁死亡。已发现许多细胞内机制可调节脂质过氧化和铁死亡，并且有大量文献表明癌细胞在以下情况下极易发生铁死亡：体外。此外，一些传统的癌症疗法，如化疗和放疗，也已被证明通过促进脂质过氧化和诱导铁死亡来有效消除癌细胞。然而，尽管人们对铁死亡及其治疗癌症的潜力充满热情，但我们的研究仍存在重大差距本提案将涉及的知识： 1）肿瘤中是否发生铁死亡，它是肿瘤发生的障碍吗？ 2) 常见的癌症突变是否会调节氧化代谢来抑制铁死亡？先前的研究因缺乏研究铁死亡的体内易处理模型而受到限制，但在这项研究中，我们提出了一种新的临床前平台来研究铁死亡作为肿瘤进展过程中的瓶颈，可以也可用于治疗（目标1）。基于这些体内模型，我们还将确定具体如何癌症突变重新连接代谢程序以维持肿瘤生长以及克服铁死亡是否是一种方法驱动疾病进展的潜在机制（目标2）。