Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma

Advanced lung adenocarcinoma obstructs airways and interferes with ventilation-perfusion relationships, leading to systemic hypoxia. This systemic hypoxemia can be exacerbated by common respiratory conditions like chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), potentially accelerating cancer progression.

Analyzing a statewide electronic health record network, pre-existing COPD or sleep apnea were found to independently predict worse survival after a lung cancer diagnosis. To further investigate the link between malignancy and hypoxia, researchers induced systemic hypoxia in mice with lung adenocarcinoma by providing low oxygen concentrations (8% inspired oxygen, 8 hours daily).

This hypoxia nearly doubled tumor multiplicity and altered cancer central carbon metabolism. Metabolomic analysis showed increased tumor glycogen levels, elevated tricarboxylic-acid cycle intermediates, and depleted glycolytic pools. Proteomic studies across cellular models and tumors revealed that systemic hypoxia promotes glycogen mobilization in the tumor through the lysosomal enzyme acid -glucosidase (GAA).

Deleting GAA in tumor cells removed the hypoxia-driven growth advantage and disrupted downstream anabolic biosynthetic pathways. Therefore, systemic hypoxia drives lung adenocarcinoma growth by mobilizing lysosomal glycogen reserves via GAA to fuel continued proliferation.