A turning point in cancer progression is metastasis, where cells break away from the primary tumor and travel throughout the body to colonize other tissues. Unlike lab-grown cells, which are nurtured in a watery solution, cancer cells in real life encounter resistance as they move through bodily fluids. Previous studies have shown how, counterintuitively, cells pick up the pace as they move through thicker solutions. However, the experiments used fluids far more viscous than those found in the body.
Now, a study published on November 2 in Nature reveals that cancer cells detect and respond to physiological levels of viscosity. In syrupy surroundings, cells trigger changes in their cellular architecture that help them overcome external forces and migrate more efficiently. They even appear to hold a memory of viscosity, continuing to move rapidly when returned to a watery medium.
“This is exciting research that adds viscosity to the list of mechanical cues that are sensed by cells and control their behavior,” says cell biologist Roberto Mayor of University College London in the UK, who was not involved in the study.
Another recent study by the same group had shown how, in confined conditions, cancer cells move by taking up water at the front of the cell and squirting it out the back, propelling themselves like octopuses through narrow spaces. To determine how cells migrate in a viscous medium in the new study, the researchers used a mathematical model previously designed to predict cellular movement and adapted it to account for higher viscosity.
The modified model predicted that external resistance triggers cells to reorganize actin—a protein that forms the internal skeleton—at the front of the cell. Subsequently, a transport protein called NHE1, recruited by actin-binding proteins, gathers on the membrane and mediates water uptake. The cell swells, pulling its membrane taut and opening TRPV4, an ion channel that is sensitive to membrane tension. Calcium ions flood into the cell and stimulate it to contract, generating a force that overcomes high viscosity to propel the cell forward.
Super-resolution microscopy of human breast cancer cells confirmed that, indeed, actin gathers on the leading edge of cells moving through thicker media. By systematically probing each component, the researchers confirmed the sequence of events within the pathway. For instance, fast migration was restored in NHE1-deficient cells by activating TRPV4, revealing that the TRPV4 channel functions downstream of water transport. “This was shocking,” says study coauthor Miguel Valverde, a molecular physiologist at Pompeu Fabra University in Barcelona, Spain, because it challenges the common assumption that ion channels are the initial responders to external events.
Valverde and his colleagues were also surprised to find that cells possessed a “memory” of their exposure to viscous conditions: Human breast cancer cells cultured for six days in high-viscosity media and then switched to watery conditions retained their speedy movement relative to cells that had been in the less-viscous solution the whole time. Similarly, breast cancer cells incubated in a sticky medium and injected into mice metastasized more widely than those pretreated in a low-viscosity solution. The cells pretreated with high-viscosity medium also moved more rapidly in zebrafish and quickly migrated out of the bloodstream in chick embryos.
The development of this “memory” appears to be dependent on TRPV4. Cells incubated for six days in a viscous solution, but that did not express the ion channel, formed fewer tumor colonies in mice than cells with functional channels that had been treated in the same way. This suggests that without the channel, pretreatment did not affect their speed within the animals.
The findings point to TRPV4 as a potential target for blocking cancer metastasis, says Valverde. “Animal knockouts for the TRPV4 channels develop normally,” he says, suggesting that healthy cells may not depend on rapid migration through viscous fluids—in which case, a therapy targeting TRPV4 might not cause significant side effects. Indeed, compared to healthy cells, the fluid surrounding tumor cells has a higher viscosity due to tumors’ tendency to degrade surrounding tissue and block lymphatic vessels. But figuring out the role—if any—that the pathway plays in normal cells is a “question that we need to address,” says study coauthor Konstantinos Konstantopoulos, a biomolecular engineer at Johns Hopkins University.
However, the findings should be interpreted with caution, says cancer biologist Jacky Goetz of INSERM in Strasbourg, France, who was not involved in the study but reviewed the manuscript for Nature. Just because cells move faster in thicker solutions doesn’t necessarily mean they are more likely to form secondary cancers, he says; tumor metastasis is a “very complex event which involves a long series of steps, some of which are independent of migration.”
Whether or not they are directly applicable in medicine, the findings may lead to changes in cell-based cancer research. “The vast majority of research performed in cell culture uses media with viscosities close to water,” says Konstantopoulos. Using media with a similar viscosity to bodily fluids may help to identify metastasis-blocking drug targets that could otherwise be missed, he says. Andrew Holle, a cancer bioengineer at the National University of Singapore who also reviewed the study for Nature, agrees. “Our goal as cancer researchers is to recapitulate the extracellular environment as closely as we can,” and media viscosity might be another factor to consider, he says.