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

项目摘要/摘要 有氧糖酵解的代谢重编程是癌症的一个标志。我们之前已经表明， 葡萄糖转运体在肺癌发生过程中的表达演变，包括癌前病变和早期病变 依赖钠-葡萄糖转运蛋白2(SGLT2)与GLUT1介导的晚期癌症 扩散。我们的母公司R01项目专注于一种假设，即葡萄糖运输的异质性反映了 异质性代谢和生物学表型：SGLT2与线粒体代谢和 早期病变增殖缓慢，GLUT1伴糖酵解代谢，晚期生长快，病情较差 分化型癌症。肺腺癌谱系的早期病变生长缓慢，可 几年后才能进展到浸润性癌症，或者可能永远不会进展。这种懒惰的行为与缺乏 Glut1和SGLT2的表达。驱动SGLT2阳性开关的分子事件惰性 GLUT1阳性侵袭性癌症的损害尚不清楚；我们正在测试代谢 重新编程和GLUT1上调在这一过程中发挥了推动作用。 肺部病毒感染导致非典型肺炎，以间质炎症和低血压为特征 用检测GLUT1的示踪剂FDG进行正电子发射断层扫描测量代谢活性 活动。然而，在无症状的患者中偶然观察到强烈的FDG嗜好损害 结果SARS-CoV-2感染呈阳性。没有全身或局部症状表明 在这些病例中，高摄取FDG不是由于大量的炎症反应，而是由于血糖增加。 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新编程类似于为癌症描述的沃堡效应，而这 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)肺泡上皮细胞感染SARS-CoV-2 细胞通过增加糖酵解和强烈的正FDG摄取来诱导代谢重编程；2)如果 在肺腺癌谱系的癌前病变中诱导代谢重编程，病毒- 从SGLT2驱动的线粒体代谢到GLUT1相关的糖酵解的诱导转换加速了 早期惰性病变进展为侵袭性、低分化性和浸润性癌症。

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.