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.

项目摘要/摘要 有氧糖酵解的代谢重编程是癌症的标志。我们以前已经表明 肺癌发生过程中葡萄糖转运蛋白的表达演变，并具有前阶段和早期病变 依靠钠 - 葡萄糖转运蛋白2（SGLT2）和高级癌症切换到GLUT1介导的 扩散。我们的父R01项目集中在葡萄糖转运的异质性反映的假设上 异质代谢和生物学表型：SGLT2与线粒体代谢和 早期病变的缓慢增殖缓慢，glut1具有糖酵解代谢和晚期生长的快速增长 分化的癌症。肺腺癌光谱的早期病变的生长缓慢，可以服用 多年的进步，或者可能永远不会发展到侵入性癌症。这种顽强的行为与不存在 glut1和sglt2的表达。从sglt2阳性懒惰的转换的分子事件 对GLUT1阳性攻击性癌症的病变尚不清楚。我们正在检验代谢的假设 重新编程和GLUT1上调在此过程中起驾驶作用。 肺病毒感染引起非典型肺炎，其特征是间质性炎症和低 通过正电子发射断层扫描与示踪剂FDG测量的代谢活性，该活性检测GLUT1 活动。但是，在无症状的患者中偶然观察到了强烈的FDG抗原病变 然后导致SARS-COV-2感染阳性。缺乏全身或局部症状表明 在这些情况下，高FDG的摄取不是由于大量炎症反应，而是葡萄糖增加 由SARS-COV-2感染的肺泡上皮细胞吸收。病毒感染会导致代谢 在宿主的上皮细胞中重新编程，类似于描述的癌症的沃堡效应，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1）SARS-COV-2感染的假设 细胞随着糖酵解的增加和强烈的FDG摄取而诱导代谢重编程； 2）如果这个 代谢重编程是在肺腺癌谱的恶性病变中诱导的，病毒 - 从SGLT2驱动的线粒体代谢转换为与GLUT1相关的糖酵解的转换会加速加速 早期，懒惰的病变的进展，侵略性，分化和侵入性癌症的进展。