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

项目总结/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， 葡萄糖转运蛋白表达在肺癌发生过程中的演变，包括癌前病变和早期病变 依赖钠-葡萄糖转运蛋白2（SGLT 2）和晚期癌症转换为GLUT 1介导的 扩散我们的父R 01项目的重点是假设葡萄糖转运的异质性反映了 异质性代谢和生物学表型：SGLT 2与线粒体代谢相关， 早期病变增殖缓慢，GLUT 1伴糖酵解代谢，晚期病变生长快， 分化型癌症肺腺癌谱的早期病变生长缓慢， 多年的进展，或可能永远不会进展到浸润性癌症。这种懒惰的行为与缺乏 GLUT 1和SGLT 2的表达。驱动SGLT 2阳性惰性药物转换的分子事件 GLUT 1阳性的侵袭性癌症的病变是未知的;我们正在测试的假设，代谢 重编程和GLUT 1上调在这一进展中起驱动作用。 肺部病毒感染引起非典型肺炎，其特征是间质性炎症和低 代谢活动，通过正电子发射断层扫描与示踪剂FDG，检测GLUT 1 活动然而，在无症状患者中偶然观察到强烈的FDG-亲合性病变， 结果为SARS-CoV-2感染阳性。没有全身或局部症状表明， 在这些病例中，高FDG摄取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。病毒感染会导致代谢性疾病 在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， 病毒复制需要重编程。 在此，我们将在体外和体内研究以下假设：1）SARS-CoV-2感染肺泡上皮细胞， 细胞诱导代谢重编程，增加糖酵解和强烈阳性FDG摄取; 2）如果这 在肺腺癌谱的癌前病变中诱导代谢重编程， 从SGLT 2驱动的线粒体代谢到GLUT 1相关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.