From embryonic development to wound healing and cancer metastasis, cells move. But like runners on a track, they won’t go very fast on a surface that’s too hard or too soft to get the right amount of grip.
“That was a key realization,” says University of Minnesota biomedical engineering professor David Odde.” Cells are very responsive to the mechanical stiffness of their environment. It affects how cells [mature from embryonic to adult form] and migrate within the body, but it was not clear how this happens.”
Odde and his colleagues have built and tested a mathematical model of how cells respond to varying degrees of stiffness in the tissues on and through which they travel. They predicted, and found, that for a given cell there is an optimal stiffness–a sweet spot–for it to move.
“It’s a Goldilocks situation,” Odde explains. “If the environment is too stiff, they can’t get a good grip. If it’s too soft, bonds with the environment slip before the cells can pull themselves forward enough.”
By applying drugs, the researchers were able to slow the movement of brain cancer cells by shifting their “sweet spot” stiffness downward, putting the cells out of sync with their environment. They hope this technique can be used someday to slow the spread of cancer or, in reverse, to speed wound healing. The research is published in the journal Nature Communications.
Engines, Clutches, and Sweet Spots
Odde and his colleagues compared cells from human brain cancer to mobile but normal cells from embryonic chick brains. The cancer cells showed a much higher “sweet spot” stiffness, like Goldilocks preferring a firmer bed. The researchers slowed the cancer cells down by following the predictions of their computer models, which were based on an understanding of the mechanics of motion.
Cells, it turns out, are like cars. They have a spinning engine that generates force, and a clutch to transfer that force to structures that grip the tissue along which they move. When the environment is stiff enough–like a paved road–they can move into higher gear, with the engine spinning faster and the clutch transferring more force to the parts that, like wheels, get more grip.
In mobile brain cells, the engine is basically a rodlike protein that acts like a conveyor belt. The building blocks of the protein are added at the forward end of the rod while at the rear end, the blocks are chopped off for recycling. This cyclical motion is driven by a second protein that acts like a motor, racheting the rod backward as it grows in the front.
The clutch is made of proteins called integrins, which extend out through the membranes that enclose cells. They transfer force by connecting the conveyor belt to the outside world and pulling on it.
The researchers’ computer simulation predicted that a fast-spinning conveyor belt would support lots of integrins, good strong grips, and a higher optimal (sweet spot) stiffness to pull against. Therefore, drugs that inhibit the motor and clutch of cancer cells should lower their sweet spot.
And that’s exactly what happened when the researchers treated the cancer cells with motor- and clutch-inhibiting drugs. When placed on gels of varying stiffness, the cells could only keep up their former speed on gels much softer than their original sweet spot. This would have the effect of hampering their movement on the stiffer materials they normally encounter in the body.
Motor- and clutch-inhibiting drugs for humans that are both effective and FDA-approved are still in development, Odde says, but with further research we may have a new way to prolong the lives of cancer patients.
David Odde is a principal investigator in the University’s new $8.2 million Physical Sciences Oncology Center.