Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination
Year: 2026
Type: article
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.
Source: Cell Reports
Authors: 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
Institutions: Johns Hopkins University, University of Alberta, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Universitat Pompeu Fabra, University of Oklahoma, Carnegie Institution for Science, Department of Embryology, OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Oklahoma Center for Adult Stem Cell Research, Breast Cancer Research Foundation, Ministerio de Ciencia, Innovación y Universidades, Alberta Cancer Foundation, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: The interplay of extracellular fluid viscosity, stiffness and confinement in regulating cell responses, Mapping the single cell state basis of metastasis in space and time, The interplay of ion transporters and cytoskeleton in breast cancer migration and metastasis, Metabolic regulation of exosome biogenesis, Viscotaxis: Novel cell migration mechanisms regulated by microenvironmental viscosity
OpenAlex ID: W7128620922