Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma

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Summary In advanced stages, lung adenocarcinoma obstructs airways and disrupts ventilation-perfusion relationships in the lung, causing systemic hypoxemia and enabling a feed-forward loop that accelerates malignancy. Systemic hypoxemia is also experienced due to common respiratory comorbidities such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), potentially accelerating malignancy. In a statewide electronic health record network, pre-existing COPD (598 matched pairs) or sleep apnea (235 matched pairs) independently predicted worse survival following incident lung cancer diagnosis. Since the mechanistic basis of the link between malignancy and hypoxia is not well understood, we created systemic hypoxia in Kras LSL- G12D/+ ;Trp53 fl/fl (KP) mice by delivering low inspired oxygen concentrations (8% inspired oxygen; 8 h daily). Hypoxia nearly doubled tumor multiplicity and selectively remodeled cancer central carbon metabolism. Spatially resolved metabolomics revealed marked tumor-compartment glycogen accumulation, elevated tricarboxylic-acid cycle intermediates, and depleted glycolytic pools. Quantitative proteomics across cellular models and autochthonous tumors demonstrated that systemic hypoxia drives glycogen mobilization selectively through the lysosomal enzyme acid α-glucosidase (GAA). Tumor-cell-autonomous deletion of GAA eliminated the hypoxia-driven growth advantage and disrupted downstream anabolic biosynthetic pathways. Thus, systemic hypoxia drives lung adenocarcinoma expansion by mobilizing lysosomal glycogen reserves through GAA to sustain proliferative growth. Highlights Systemic hypoxia acts as an intrinsic driver of lung adenocarcinoma progression. Controlled systemic hypoxia doubles tumor multiplicity and reprograms cancer metabolism. Hypoxic tumors mobilize glycogen via lysosomal GAA independently of HIF-1α stabilization. Tumor-cell-autonomous deletion of GAA eliminates the hypoxia-mediated growth advantage in vivo. Pre-existing COPD and sleep apnea exacerbate hypoxemic burden and worsen clinical survival. eTOC Blurb Lung tumors compromise pulmonary gas exchange, driving systemic hypoxemia that accelerates malignancy. Comorbidities such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea compound this hypoxemic burden. Clarke et al. isolate systemic hypoxia in mice, showing it doubles lung tumor multiplicity by inducing glycogen degradation through lysosomal acid α-glucosidase (GAA). Deleting GAA eliminates this hypoxic growth advantage.

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