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.

Public Health Relevance

Lung cancer starts as pre-malignant lesions that progress very slowly, or may never progress, to advanced cancer. Glucose metabolism plays an important role in the progression from pre-malignant lesions to advanced cancer. Here, we investigate the hypothesis that infection of pre-malignant lesions with the novel coronavirus increases glucose metabolism and thus accelerates the progression to advanced cancer in cases that would otherwise be asymptomatic and never progress to cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA237401-01A1S2
Application #
10199384
Study Section
Program Officer
Willis, Kristine Amalee
Project Start
2020-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095