By Deborah Borfitz
January 19, 2022 | Researchers at the University of Michigan (U-M) have made the connection between cellular motility—with a known connection to tumor metastasis—and the shape-shifting behavior of cancer cells to become more “missile-like” and thus better able to make the voyage from one site in the body to another. The newly acquired characteristic arises when epithelial cells morph into mesenchymal cells, but the transition can’t be seen if the cells are all held hostage on a glass microscope slide, says Raoul Kopelman, U-M professor of chemistry, physics, applied physics, biophysics, biomedical engineering and chemical biology.
To study these cell dynamics requires “cell magnetorotation,” a method developed by the research team a decade ago. The technique employs a microfluidic device with 1,000 or so tiny compartments, each accommodating a single, free-floating cancer cell whose shape-shifting behavior is tracked using magnetic nanoparticles, fluorescent microscopy, and artificial intelligence to classify the phenotypes.
The device was used in a study, recently published in PLOS One (DOI: 10.1371/journal.pone.0259462), to show that only cancer cells that have undergone epithelial to mesenchymal transition (EMT), acquire the missile-like shape to become more mobile and thus more lethal. In other words, a cell’s morphological shape is strongly correlated with its biological behavior, Kopelman says.
For the study, researchers first forced a human prostate cancer cell line to go through EMT and identified which cells underwent the transition and which did not. They then showed they could distinguish highly mobile from nonmigrating breast cancer cells within the same sample.
A map of the plasticity of a tumor is possible based on how many individual cancer cells adopt the incriminating missile-like shape when tested with the device, he continues. Applied to clinical practice, this might give oncologists a means to better assess the aggressiveness of cancer and the urgency to operate.
Real-Time Monitoring
The magnetorotation method was the “easy part” of the study because researchers were familiar with the technique, says Kopelman. A commercially available solution of magnetic iron oxide nanoparticles gets dropped into each compartment of the device, which harmlessly enters the cells and causes them to gently rotate in a magnetic field generated by a coil of wire positioned around the unit.
Their rotation doesn’t affect the shape of the cancer cells, but it does permit them to shape-shift much as they would inside the body, he says. Object recognition and machine learning are used to “follow each cell’s rotation and put the whole picture together… based on how they behave.”
Used in combination, the two algorithms can classify the shape features of the rotating cells and readily split them into two distinct populations—metastatic and non-metastatic, Kopelman notes. For the study, the prototype device continuously measured shape dynamics in real time over about three hours.
Kopelman credits his adoption of the shape-shifting terminology to the science fiction movies he enjoys watching with his granddaughters. But those fictional characters, from werewolves to wizards with fascinating powers to take on alternate forms, are “obviously a different class of shape-shifters,” he chuckles.
Ultimately, Kopelman says, a specialized instrument for the serious business of monitoring shape-shifting cancer cells might be mass-produced by an interested outside party. The marketed device, as envisioned, would join the diagnostic arsenal of hospitals where patient samples are already being routinely processed.
“As far as I know, there is no such device anywhere else in the world at this point,” Kopelman adds. Its utility would extend to analyzing the metastatic potential of tumors in mice, for research purposes, as well as human subjects with solid-tumor cancers or xenografts such as mice with implanted cancer cells taken from a given patient.