SGLT2-mediated glucose uptake defines early metabolic reprogramming in lung adenocarcinoma

Abstract

Abstract The metabolic reprogramming taking place during early lung adenocarcinoma (LUAD) progression remain poorly understood. While early-stage LUAD frequently demonstrates low 18F-2-fluorodeoxyglucose (18FDG) uptake on positron emission tomography (PET), it is unclear whether this reflects metabolic quiescence or alternative glucose utilization pathways. We hypothesized that early lesions are metabolically active but preferentially utilize sodium-glucose cotransporter 2 (SGLT2), a non-canonical glucose transporter with low 18FDG affinity. This study investigates metabolic activity in early-stage LUAD and glucose transporter expression patterns across the adenocarcinoma spectrum. LDH, SGLT2 and GLUT1 expression were evaluated by immunohistochemistry in human lung cancers and compared with normal lung and benign inflammation. Expression levels were correlated with structural and radiologic features including tumor size, invasion, histology, radiographic features and PET avidity. Glycolysis was elevated in premalignant and early LUAD as indicated by LDH expression. SGLT2 was highly expressed in preinvasive and minimally invasive LUAD compared to normal lung and invasive tumors. Conversely, GLUT1 was upregulated in invasive, high-grade tumors. Radiographically, SGLT2 expression was associated with subsolid nodules and low PET avidity, while GLUT1 expression was higher in nodules with a solid component and high 18FDG avidity. Notably, SGLT2 was not elevated in inflammatory lesions compared to normal lung, unlike GLUT1, which was frequently upregulated in inflammation. Early lung adenocarcinoma lesions exhibit aerobic glycolysis despite low FDG avidity and preferentially utilize SGLT2-mediated glucose uptake. These findings highlight a distinct metabolic profile in early LUAD and underscore the need for alternative imaging modalities to enhance the detection of early lesions.