Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination

Se Jong Lee; Alice Amitrano; Qinling Yuan; Debanik Choudhury; Konstantin Stoletov; Bhawana Agarwal; Avery Tran; Inês Godet; James McCann; Ryan Huizar; Selma A Serra; Pol Picón-Pagès; Norbert Valles; Sangmoo Jeong; Stavroula Sofou; Chen-Ming Fan; John D Lewis; Sean X Sun; Andrew J Ewald; Daniele M Gilkes; Vivek K Bajpai; Miguel A Valverde; Konstantinos Konstantopoulos

doi:10.1016/j.celrep.2026.116970

Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination

Cell Rep. 2026 Feb 24;45(2):116970. doi: 10.1016/j.celrep.2026.116970. Epub 2026 Feb 11.

Authors

Se Jong Lee¹, Alice Amitrano¹, Qinling Yuan¹, Debanik Choudhury¹, Konstantin Stoletov², Bhawana Agarwal¹, Avery Tran¹, Inês Godet³, James McCann⁴, Ryan Huizar⁴, Selma A Serra⁵, Pol Picón-Pagès⁵, Norbert Valles⁶, Sangmoo Jeong¹, Stavroula Sofou⁷, Chen-Ming Fan⁸, John D Lewis², Sean X Sun⁹, Andrew J Ewald¹⁰, Daniele M Gilkes¹¹, Vivek K Bajpai¹², Miguel A Valverde⁵, Konstantinos Konstantopoulos¹³

Affiliations

¹ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.
² Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
³ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁴ Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁵ Laboratory of Molecular Physiology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
⁶ School of Sustainable Chemical, Biological and Materials Engineering, University of Oklahoma, Norman, OK 73019, USA.
⁷ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁸ Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA.
⁹ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
¹⁰ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Giovanis Institute for Translational Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
¹¹ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
¹² School of Sustainable Chemical, Biological and Materials Engineering, University of Oklahoma, Norman, OK 73019, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Dermatology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
¹³ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address: konstant@jhu.edu.

PMID: 41686638
DOI: 10.1016/j.celrep.2026.116970

Abstract

Acidosis is a hallmark of the tumor microenvironment and has been linked to aggressive cancer behavior, characterized by increased migration, invasion, and metastasis. We herein demonstrate that short-term exposure (24-72 h) to acidic extracellular pH (pH_e = 6.4) suppresses cell proliferation, metabolism, dissociation from tumor spheroids, and migration in vitro as well as extravasation in chick embryos and mice. Acidosis acutely inhibits motility by downregulating the activity of sodium-hydrogen exchanger isoform-1 (NHE1), which in turn suppresses phosphatidylinositol 3-kinase (PI3K)/Akt. PI3K/Akt inhibition blocks Yes-associated protein (YAP) translocation to the nucleus, reducing NHE1 and integrin-linked kinase (ILK) expression. The resulting reduction in NHE1-/ILK-dependent migration and ATP production is rescued by hypoxia across cell types. While certain cancer cells can adapt to long-term (>3 weeks) acidosis and acquire an aggressive phenotype, acidosis-induced adaptation is not universal and depends on the cell's ability to restrain reactive oxygen species overproduction via fatty acid oxidation.

Keywords: Akt; CP: cancer; CP: metabolism; NHE1; YAP; acidosis; cancer; glycolysis; hypoxia; integrin-linked kinase; migration; reactive oxygen species.

MeSH terms

Acidosis* / metabolism
Acidosis* / pathology
Animals
Cell Hypoxia
Cell Line, Tumor
Cell Movement
Cell Proliferation
Chick Embryo
Humans
Hydrogen-Ion Concentration
Mice
Neoplasms* / metabolism
Neoplasms* / pathology
Phosphatidylinositol 3-Kinases / metabolism
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Reactive Oxygen Species / metabolism
Signal Transduction
Sodium-Hydrogen Exchanger 1 / metabolism
Tumor Microenvironment

Substances

Sodium-Hydrogen Exchanger 1
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Reactive Oxygen Species
Protein Serine-Threonine Kinases

Abstract

MeSH terms

Substances

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