Investigating the effect of SARS-CoV-2 infection on metabolic reprogramming in lung cancer

研究 SARS-CoV-2 感染对肺癌代谢重编程的影响

• 批准号: 10199384
• 负责人: Claudio Scafoglio
• 金额: $ 14.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199384
• 关键词: 2019-nCoV; 3-Dimensional; Adenocarcinoma Cell; Advanced Malignant Neoplasm; Automobile Driving; Bacterial Infections; Behavior; Biological; Biological Assay; Cell Differentiation process; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Diffusion; Engineering; Epithelial Cells; Event; Glucose Transporter; Glycolysis; Growth; Heterogeneity; Human; In Vitro; Indolent; Infection; Inflammation; Inflammatory Response; Investigation; Lesion; Lesion by Stage; Lobar; Lung; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Metabolic; Metabolism; Modeling; Molecular; Morphology; Mutation; Neutrophil Activation; Normal Cell; Organoids; Parents; Patients; Phenotype; Play; Positron-Emission Tomography; Predisposition; Premalignant Cell; Proteins; Reporting; Resected; Role; SLC2A1 gene; Sampling; Sodium; Symptoms; TP53 gene; Testing; Tracer; Up-Regulation; Viral Pneumonia; Virus; Virus Diseases; Virus Replication; Warburg Effect; Well Differentiated Lesion; aerobic glycolysis; airway epithelium; alveolar epithelium; atypical pneumonia; cancer cell; cancer invasiveness; epithelial to mesenchymal transition; fluorodeoxyglucose; glucose metabolism; glucose transport; glucose uptake; in vitro Model; in vivo; interstitial; lung carcinogenesis; metaplastic cell transformation; mitochondrial metabolism; novel; novel coronavirus; premalignant; therapeutic target; three-dimensional modeling; tumor; uptake

PROJECT SUMMARY/ABSTRACT Metabolic reprogramming with aerobic glycolysis is a hallmark of cancer. We have previously shown that glucose transporter expression evolves during lung carcinogenesis, with pre-malignant and early-stage lesions relying on sodium-glucose transporter 2 (SGLT2) and advanced cancers switching to GLUT1-mediated diffusion. Our parent R01 project is focused on the hypothesis that heterogeneity of glucose transport reflects heterogeneous metabolic and biological phenotypes: SGLT2 is associated with mitochondrial metabolism and slow proliferation in early lesions, GLUT1 with glycolytic metabolism and fast growth in advanced, poorly differentiated cancers. Early lesions of the lung adenocarcinoma spectrum are slow growing and can take years to progress, or may never progress, to invasive cancer. This indolent behavior correlates with absence of GLUT1 and expression of SGLT2. The molecular events that drive the switch from SGLT2-positive indolent lesions to GLUT1-positive aggressive cancers are unknown; we are testing the hypothesis that metabolic reprogramming and GLUT1 upregulation play a driving role in this progression. Pulmonary viral infections cause atypical pneumonia, characterized by interstitial inflammation and low metabolic activity as measured by positron emission tomography with the tracer FDG, which detects GLUT1 activity. However, intensely FDG-avid lesions have been observed incidentally in asymptomatic patients who then resulted positive for SARS-CoV-2 infection. The absence of systemic or local symptoms suggests that the high FDG uptake is not due in these cases to massive inflammatory responses, but to increased glucose uptake by alveolar epithelial cells infected by SARS-CoV-2. Viral infections can cause metabolic reprogramming in the host epithelial cells similar to the Warburg effect described for cancer, and this reprogramming is required for viral replication. Here, we will investigate in vitro and in vivo the hypotheses that 1) SARS-CoV-2 infection in alveolar epithelial cells induces metabolic reprogramming with increased glycolysis and intensely positive FDG uptake; 2) if this metabolic reprogramming is induced in pre-malignant lesions of the lung adenocarcinoma spectrum, the virus- induced switch from SGLT2-driven mitochondrial metabolism to GLUT1-associated glycolysis accelerates the progression of early-stage, indolent lesions to aggressive, poorly differentiated and invasive cancers.

项目概要/摘要 有氧糖酵解的代谢重编程是癌症的标志。我们之前已经证明了 葡萄糖转运蛋白表达在肺癌发生过程中不断演变，包括癌前病变和早期病变 依赖钠-葡萄糖转运蛋白 2 (SGLT2) 和晚期癌症转向 GLUT1 介导 扩散。我们的母体 R01 项目重点关注葡萄糖转运的异质性反映的假设 异质代谢和生物表型：SGLT2 与线粒体代谢和 早期病变增殖缓慢，GLUT1 具有糖酵解代谢作用，晚期病变生长快速 分化的癌症。肺腺癌谱系的早期病变生长缓慢，可能需要 数年进展或可能永远不会进展为侵袭性癌症。这种懒惰的行为与缺乏 GLUT1 和 SGLT2 的表达。驱动 SGLT2 阳性惰性转变的分子事件 GLUT1 阳性侵袭性癌症的病变尚不清楚；我们正在检验新陈代谢的假设 重编程和 GLUT1 上调在这一进程中发挥着驱动作用。 肺部病毒感染引起非典型肺炎，其特点是间质炎症和低度感染。 使用示踪剂 FDG 通过正电子发射断层扫描测量代谢活动，可检测 GLUT1 活动。然而，在无症状患者中偶然观察到强烈的 FDG 强烈病变，这些患者 随后检测结果呈 SARS-CoV-2 感染阳性。没有全身或局部症状表明 在这些情况下，高 FDG 摄取并不是由于大量炎症反应，而是由于葡萄糖增加 被 SARS-CoV-2 感染的肺泡上皮细胞摄取。病毒感染可引起代谢 宿主上皮细胞中的重编程类似于癌症中描述的瓦尔堡效应，并且这 病毒复制需要重新编程。 在这里，我们将在体外和体内研究以下假设：1）肺泡上皮中的 SARS-CoV-2 感染 细胞诱导代谢重编程，糖酵解增加，FDG 摄取呈强阳性； 2）如果这个 代谢重编程是在肺腺癌谱系的癌前病变中诱导的，病毒- 诱导从 SGLT2 驱动的线粒体代谢转变为 GLUT1 相关的糖酵解，加速了 早期惰性病变进展为侵袭性、低分化和侵袭性癌症。