Extracellular fluid viscosity enhances cell migration and cancer dissemination

Kaustav Bera, Alexander Kiepas, Inês Godet, Yizeng Li, Pranav Mehta, Brent Ifemembi, Colin D. Paul, Anindya Sen, Selma A. Serra, Konstantin Stoletov, Jiaxiang Tao, Gabriel Shatkin, Se Jong Lee, Yuqi Zhang, Adrianna Boen, Panagiotis Mistriotis, Daniele M. Gilkes, John D. Lewis, Chen-Ming Fan, Andrew P. Feinberg, Miguel A. Valverde, Sean X. Sun and Konstantinos Konstantopoulos ()
Additional contact information
Kaustav Bera: Johns Hopkins University
Alexander Kiepas: Johns Hopkins University
Inês Godet: Johns Hopkins University
Yizeng Li: Binghamton University, SUNY
Pranav Mehta: Johns Hopkins University
Brent Ifemembi: Johns Hopkins University
Colin D. Paul: National Cancer Institute, National Institutes of Health
Anindya Sen: Johns Hopkins University
Selma A. Serra: Universitat Pompeu Fabra
Konstantin Stoletov: University of Alberta
Jiaxiang Tao: Carnegie Institution for Science
Gabriel Shatkin: Johns Hopkins University
Se Jong Lee: Johns Hopkins University
Yuqi Zhang: Johns Hopkins University
Adrianna Boen: Johns Hopkins University
Panagiotis Mistriotis: Auburn University
Daniele M. Gilkes: Johns Hopkins University
John D. Lewis: University of Alberta
Chen-Ming Fan: Carnegie Institution for Science
Andrew P. Feinberg: Johns Hopkins University School of Medicine
Miguel A. Valverde: Universitat Pompeu Fabra
Sean X. Sun: Johns Hopkins University
Konstantinos Konstantopoulos: Johns Hopkins University

Nature, 2022, vol. 611, issue 7935, 365-373

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05394-6

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