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Extracellular fluid viscosity enhances cell migration and cancer dissemination.
Bera, Kaustav; Kiepas, Alexander; Godet, Inês; Li, Yizeng; Mehta, Pranav; Ifemembi, Brent; Paul, Colin D; Sen, Anindya; Serra, Selma A; Stoletov, Konstantin; Tao, Jiaxiang; Shatkin, Gabriel; Lee, Se Jong; Zhang, Yuqi; Boen, Adrianna; Mistriotis, Panagiotis; Gilkes, Daniele M; Lewis, John D; Fan, Chen-Ming; Feinberg, Andrew P; Valverde, Miguel A; Sun, Sean X; Konstantopoulos, Konstantinos.
Affiliation
  • Bera K; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Kiepas A; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • Godet I; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Li Y; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • Mehta P; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Ifemembi B; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Paul CD; Department of Biomedical Engineering, Binghamton University, SUNY, Binghamton, NY, USA.
  • Sen A; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Serra SA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • Stoletov K; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Tao J; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • Shatkin G; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Lee SJ; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Zhang Y; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • Boen A; Laboratory of Molecular Physiology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
  • Mistriotis P; Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
  • Gilkes DM; Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA.
  • Lewis JD; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Fan CM; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Feinberg AP; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • Valverde MA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Sun SX; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
  • Konstantopoulos K; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
Nature ; 611(7935): 365-373, 2022 Nov.
Article in En | MEDLINE | ID: mdl-36323783
ABSTRACT
Cells respond to physical stimuli, such as stiffness1, fluid shear stress2 and hydraulic pressure3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer5. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.
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Full text: 1 Database: MEDLINE Main subject: Viscosity / Cell Movement / Extracellular Fluid / Neoplasm Metastasis / Neoplasms Limits: Animals Language: En Year: 2022 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Viscosity / Cell Movement / Extracellular Fluid / Neoplasm Metastasis / Neoplasms Limits: Animals Language: En Year: 2022 Type: Article