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

PROJECT SUMMARY/Abstract: Metabolic reprogramming with aerobic glycolysis is a hallmark of cancer. We have previously shown thatglucose transporter expression evolves during lung carcinogenesis, with pre-malignant and early-stage lesionsrelying on sodium-glucose transporter 2 (SGLT2) and advanced cancers switching to GLUT1-mediateddiffusion. Our parent R01 project is focused on the hypothesis that heterogeneity of glucose transport reflectsheterogeneous metabolic and biological phenotypes: SGLT2 is associated with mitochondrial metabolism andslow proliferation in early lesions, GLUT1 with glycolytic metabolism and fast growth in advanced, poorlydifferentiated cancers. Early lesions of the lung adenocarcinoma spectrum are slow growing and can takeyears to progress, or may never progress, to invasive cancer. This indolent behavior correlates with absence ofGLUT1 and expression of SGLT2. The molecular events that drive the switch from SGLT2-positive indolentlesions to GLUT1-positive aggressive cancers are unknown; we are testing the hypothesis that metabolicreprogramming and GLUT1 upregulation play a driving role in this progression.Pulmonary viral infections cause atypical pneumonia, characterized by interstitial inflammation and lowmetabolic activity as measured by positron emission tomography with the tracer FDG, which detects GLUT1activity. However, intensely FDG-avid lesions have been observed incidentally in asymptomatic patients whothen resulted positive for SARS-CoV-2 infection. The absence of systemic or local symptoms suggests that thehigh FDG uptake is not due in these cases to massive inflammatory responses, but to increased glucoseuptake by alveolar epithelial cells infected by SARS-CoV-2. Viral infections can cause metabolicreprogramming in the host epithelial cells similar to the Warburg effect described for cancer, and thisreprogramming is required for viral replication.Here, we will investigate in vitro and in vivo the hypotheses that 1) SARS-CoV-2 infection in alveolar epithelialcells induces metabolic reprogramming with increased glycolysis and intensely positive FDG uptake; 2) if thismetabolic 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 theprogression of early-stage, indolent lesions to aggressive, poorly differentiated and invasive cancers.