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bioRxiv · 10.1101/2020.10.28.359018

Cycling hypoxia selects for constitutive HIF stabilization

Pressley, M.·Gallaher, J. A.·Brown, J. S.·Tomaszewski, M. R.·Borad, P.·Damaghi, M.·Gillies, R. J.·Whelan, C. J.
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Abstract

Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF- stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF- stabilization becomes constitutive even under normoxia, a condition known as pseudohypoxia. Herein, we develop a mathematical model that predicts the effects of fluctuating levels of oxygen availability on stabilization of HIF- and its client proteins based on fitness. The model shows that facultative regulation of HIF- always promotes greater cell fitness than constitutive regulation. However, cell fitness is nearly identical regardless of HIF- regulation strategy when there are rapid periodic fluctuations in oxygenation. Furthermore, the model predicts that stochastic changes in oxygenation favor facultative HIF- regulation. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia.

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Pressley, M., Gallaher, J. A., Brown, J. S., Tomaszewski, M. R., Borad, P., Damaghi, M., Gillies, R. J., Whelan, C. J.. 2020-10-28. Cycling hypoxia selects for constitutive HIF stabilization. https://doi.org/10.1101/2020.10.28.359018

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