Higher viscosity of extracellular fluid promotes cancer dissemination

New research shows that the more viscous or flow-resistant the extracellular fluid that surrounds a cell, the more quickly cancer cells can migrate from the primary tumor to other parts of the body.

We have determined how cells sense and respond to physiologically relevant levels of fluid viscosity commonly found in healthy and diseased patients. We also showed that cells are capable of forming memories when exposed to increased liquid viscosity. We believe that these findings will lead researchers in fields other than cancer mechanobiology to view fluid viscosity as an important physical cue that modulates cellular responses. “

Konstantinos Konstantopoulos, Ph.D., principal investigator of the study, William H. Schwarz Professor of Chemical and Biomolecular Engineering, Appointed Biomedical Engineering and Oncology, Johns Hopkins Kimmel Cancer Center Invasion and Metastasis Program is a member of

The findings, which reveal a new mechanism that promotes cancer cell dissemination, were published Nov. 2. Nature and provide a framework for ongoing research that may ultimately lead to the identification of potential new targets for combating cancer metastasis.

Deregulation of body fluid viscosity has been correlated with many diseases for nearly half a century, but so far research on cancer cell dissemination has mainly been performed using low-viscosity liquids similar to water. has been around for a long time, explains Dr. Kaustav Bera, a recent graduate. From Konstantopoulos Lab and the first author of the study. “It was expected that cancer cells would not migrate or metastasize as efficiently because there is greater resistance in more viscous fluids, but we have shown that the opposite is true.” she says.

Researchers have shown how cells sense and respond to physical cues of increased viscosity, and how the cytoskeleton, which controls cell shape and subcellular organization, and participates in cell motility, functions as an ion channel. and to cooperate with ion transporters. Charged molecules across cell membranes – mediate efficient movement at high viscosities.

Extracellular viscosity is elevated by degradation of large proteins secreted by both normal and cancer cells and by impaired lymphatic drainage by primary tumor growth. Researchers found that a higher resistance environment promoted the formation of denser actin networks. This promotes local concentration of ion transporters that cooperate with water channels to facilitate water uptake, promote cell swelling and increase membrane tension. At the leading edge of the cell, this increase in membrane tension activates signaling pathways. The signaling pathway involves an ion channel called TRPV4 that senses physical cues. Fluid viscosity tells cells to open her TRPV4 channels, facilitating calcium uptake. This increases the force-generating capacity of the cells, ultimately resulting in faster cell movement.

“It’s like your cells under high viscosity go to the gym and train hard and develop your muscles (actin and myosin). This allows you to perform better and reach your final destination faster.” Research collaborator Selma Serra, Ph.D. – Pompeu, Barcelona, ​​Spain He is an author and researcher at the University of Fabra.

The mechanosensing cascade was previously thought to start with ion channels like TRPV4, says Alex Kiepas, Ph.D., a postdoctoral fellow and second author of the study. “We found that viscous sensing begins with the formation of denser, highly branched actin, and that TRPV4 activation is indeed downstream of actin,” he says.

When the researchers knocked down TPRV4, it blocked the cells’ faster movement and ability to form memories in response to pre-exposure to high viscosity. The researchers used a 3-day-old zebrafish embryo model to show that memory of elevated viscosity allows cells to move faster in vivo through blood vessels. They also used chicken embryos and mouse models to demonstrate that memory promotes extravasation of cancer cells, resulting in more distant metastatic colonies, through a process called extravasation. Did.

Konstantopoulos investigated in animal models how primary tumors and cancer cells disseminated from primary tumors respond to local changes in extracellular fluid viscosity during disease progression and invasion of the tissue microenvironment. He said it would be beneficial to investigate. To address this issue, it is important to develop and optimize biosensors capable of imaging cancer cells in live animals and measuring the viscosity of extracellular fluids in real time. They also plan to investigate whether extracellular viscosity influences other physiologically relevant cellular processes.

Other researchers involved in the study were Ines Godet, Pranav Mehta, Brent Ifemenbi, Aninda Sen, Se Jong Lee, Yuki Chan, Gabriel Shatkin, Adriana Bowen, and others at Johns Hopkins University. They were Daniel M. Gilks, Andrew P. Feinberg, and Sean X. Sun. University. Collaborators from other centers include Yizeng Li, Colin D. Paul, Konstantin Stoletov, Jiaxiang Tao, Panagiotis Mistriotis, John D. Lewis, Chen-Ming Fan, and Miguel A. Valverde.https://www.hopkinsmedicine.org/”>