2. Academic Validation
  3. Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination

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.
Se Jong Lee 1,  Alice Amitrano 1,  Qinling Yuan 1,  Debanik Choudhury 1,  Konstantin Stoletov 2,  Bhawana Agarwal 1,  Avery Tran 1,  Inês Godet 3,  James McCann 4,  Ryan Huizar 4,  Selma A Serra 5,  Pol Picón-Pagès 5,  Norbert Valles 6,  Sangmoo Jeong 1,  Stavroula Sofou 7,  Chen-Ming Fan 8,  John D Lewis 2,  Sean X Sun 9,  Andrew J Ewald 10,  Daniele M Gilkes 11,  Vivek K Bajpai 12,  Miguel A Valverde 5,  Konstantinos Konstantopoulos 13
Affiliations

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: [email protected].
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 (pHe = 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138565
    99.89%, YAP1/TAZ-TEAD Inhibitor
    YAP