Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma
- 1Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA
Abstract
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 KrasLSL-G12D/+;Trp53fl/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 -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.
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BibTeX
@misc{clarke2026systemic,
title = {{Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma}},
author = {H. A. Clarke and C. J. Shedlock and H. Peters and T. R. Hawkinson and D. D. Kooser and O. Janzen and A. Varma and F. Bucco and C. M. Soto and R. Larson and A. M. Ryan and T. Medina and R. A. Ribas and C. M. Calulot and L. Wu and J. Russ and S. Florea and Y. Wang and K. B. Basso and D. B. Allison and M. Corti and D. D. Fuller and W. J. Alilain and G. S. Mitchell and B. J. Byrne and C. W. Vander Kooi and Y. Guo and M. S. Gentry and R. C. Sun},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748693},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748693v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma
AU - H. A. Clarke
AU - C. J. Shedlock
AU - H. Peters
AU - T. R. Hawkinson
AU - D. D. Kooser
AU - O. Janzen
AU - A. Varma
AU - F. Bucco
AU - C. M. Soto
AU - R. Larson
AU - A. M. Ryan
AU - T. Medina
AU - R. A. Ribas
AU - C. M. Calulot
AU - L. Wu
AU - J. Russ
AU - S. Florea
AU - Y. Wang
AU - K. B. Basso
AU - D. B. Allison
AU - M. Corti
AU - D. D. Fuller
AU - W. J. Alilain
AU - G. S. Mitchell
AU - B. J. Byrne
AU - C. W. Vander Kooi
AU - Y. Guo
AU - M. S. Gentry
AU - R. C. Sun
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748693
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748693v1
AB - 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 KrasLSL-G12D/+;Trp53fl/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 -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.
ER -