Nature: Challenge the norm! The higher the viscosity of the extracellular fluid, the easier it is for cancer cells to metastasize from the primary tumor to other parts of the body

In a new study, researchers from research institutions such as Johns Hopkins University in the United States and Pompeu Fabra University in Spain found that the higher the viscosity (i.
e.
, flow resistance) of the extracellular fluid surrounding the cells, the easier it is for cancer cells to metastasize from the primary tumor to other
parts of the body 。 The findings were published in the November 10, 2022 issue of Nature as "Extracellular fluid viscosity enhances cell migration and cancer dissemination.
"

Dr.
Konstantinos Konstantopoulos, corresponding author and member of the Invasion and Metastasis Program at Johns Hopkins University Kingmel Cancer Center, said, "We deciphered how cells sense and respond to physiologically relevant extracellular fluid viscosity levels
common in healthy and sick patients.
We also found that cells have the ability to form memories
when previously exposed to elevated extracellular fluid viscosity.
We believe these findings will force researchers in fields other than cancer mechanobiology to view extracellular fluid viscosity as a key physical cue
for regulating cellular responses.
" ”

The findings reveal a new mechanism that facilitates the spread of cancer cells and provide a framework for ongoing research that could eventually lead to the identification of potential new targets that attack cancer metastasis
.

Dr.
Kaustav Bera, the first author of the paper and a recent graduate of Konstantopoulos' laboratory, explains that although viscosity disorders of body fluids have been associated with many diseases for nearly half a century, research on the spread of cancer cells to date has mainly been conducted
using low-viscosity liquids similar to water.
"The expectation was that cancer cells would not metastasize efficiently because of more resistance in a thicker fluid, but we found the opposite
," she said.
”

These authors reveal physical cues about how cells sense and respond to increased viscosity, and how the cytoskeleton, which controls cell shape and intracellular structure and participates in cell movement, works with ion channels and ion transporters--- protein --- that guide charged molecules through the cell membrane to regulate efficient migration
at high viscosities.

Extracellular fluid viscosity increases
with degradation of large proteins secreted by normal and cancer cells and impaired lymphatic drainage due to primary tumor growth.
The authors found that a higher resistance environment drives the formation of a denser actin network, which promotes local enrichment of ion transporters that cooperate with water channels to promote water uptake, promote cell expansion, and increase membrane tone
.
At the cell's leading edge, this increased membrane tension activates a signaling pathway that includes an ion channel
called TRPV4 that senses physical cues.
Extracellular fluid viscosity instructs the cell to turn on its TRPV4 channel, promoting calcium uptake, which enhances the cell's ability to generate strength and ultimately pushes the cell to move
faster.

Dr Selma Serra, a co-author and researcher at Pompeu Fabra University, said, "It's like cells with high viscosity going to the gym for high-intensity training and growing muscle (actin and myosin), which improves their performance in order to reach their final destination
faster.
" ”

Co-author Dr.
Alex Kiepas of Johns Hopkins University said it was previously thought that mechanically induced cascades began
with the TRPV4 plasma channel.
"We found that viscosity sensing begins with the formation of more dense and highly branched actin, and activation of TRPV4 is actually downstream
of actin," he said.
”

When these authors knocked out TPRV4, they blocked the faster movement of the cells, as well as their ability to form memories when previously exposed to
high-viscosity extracellular fluid.
Using a 3-day-old zebrafish embryo model, they showed that memory of elevated viscosity allowed cells to move
faster through blood vessels in the body.

Extracellular fluid viscosity enhances cell migration and promotes ARP2/3-mediated dense actin network formation
at the leading edge.
Image from Nature, 2022, doi:10.
1038/s41586-022-05394-6
.

Using chicken embryos and mouse models, they also showed that this memory can strengthen the spread of cancer cells outside blood vessels through a process called extravasation and lead to more distant metastatic colonies
.

Konstantopoulos said it would be interesting
to study in laboratory animal models how primary tumors and cancer cells that have spread from primary tumors respond to local changes in extracellular fluid viscosity during disease progression and during infiltration of the tissue microenvironment.

The development and optimization of biosensors capable of measuring extracellular fluid viscosity in real time, while imaging cancer cells in living animals, is critical
to addressing this.
They also plan to investigate whether extracellular fluid viscosity affects other physiologically relevant cellular processes
.
(Biovalley Bioon.
com)

Resources:

Kaustav Bera et al.
 Extracellular fluid viscosity enhances cell migration and cancer dissemination, Nature, 2022, doi:10.
1038/s41586-022-05394-6.