In cells, more persistent leaders drive response of group

Cells in a group mimic birds migrating in a flock, giving insight into how aggressive tumor cells invade the body.

Above are simulated configurations of cell sheets corresponding to cell repolarization intervals at 1, 6 and 10 minutes. The cell sheets show randomly chosen polarization directions after every repolarization time interval at different time points over a
When birds migrate, one bird takes the lead and the rest of the flock follows in a group. When the flock changes direction, a new bird takes the lead. Likewise, cells follow a similar pattern, giving researchers a clue into how aggressive tumor cells invade the body or how organs are formed.

When cells move together in groups, their movement regulates process in disease, development and regeneration, such as wound healing. Each cell has a pole that determines its front and back, determines the cell's shape and which cells become leaders of a group. The more often cells change directions determines their persistence — the more often they change direction, the less persistent they are.

Using models and experiments, Amit Pathak, assistant professor of mechanical engineering & materials science in the School of Engineering & Applied Science at Washington University in St. Louis, and his group are the first to look at the properties of these aggressive leader cells and how their polarization affects their behavior. Results of the research were published online in Biophysical Journal Nov. 16.

Pathak's team devised a mathematical model for varying cell polarity within a cell group and compared predictions with experimental measurements. Jairaj Mathur, a doctoral student in Pathak's lab, implemented the new biomechanical dynamics of polarity within a computational framework and predicted that more persistently polarized leader cells cause more chaotic migration and crooked shapes of the cell group.

Using time-lapse microscopy of mammary epithelial cells at high temporal resolution, Bapi Sarker, a postdoctoral fellow in Pathak's lab, found that the leader cells chose their polarity at the front, became elongated into an oval shape and remained at the front longer without changing direction, known as a repolarization interval. They also infrequently interacted with the other cells in the core of the group, which changed directions more frequently.

"Because of the very high repolarization interval, the polarity of these leader cells is more persistent than that of cells in the core," Pathak said. "Because of this, the shape of the cell group becomes very rough and migrates much faster in most cases."

Normal cells maintained their round shape and stayed within the crowded core of the cell cluster.

Having a rough edge to the shape of the cell cluster could make it easier for the leader cells to invade tissue, Pathak said.

"If the leading edge is nice and straight, it won't be able to adapt to the tissue and invade," he said. "But if the front of the leading edge is rough and changes dynamically, it would be better at adapting to a crevice in the tissue, which might lead to more invasion."

Pathak said while this finding doesn't yet have a direct physiological relevance, the research indicates that these aggressive leader cells would be a benefit to human development by helping to create new organs, but could be damaging if in invasive tumor cells.

"Our prediction is that the leader cells really have to be in the front to be able to do anything," Pathak said. "If there is some therapeutic target that doesn't allow the leader cells to come to the front, then the invasion will be far less destructive."

This ascribes a new cellular property, namely persistence of direction, to leader cells.

"In most therapies, the aggressive cells are targeted for killing," he said. "But, it is possible that the aggressive leader cells may not have to be killed if there were a more sophisticated target that disallows them from coming to the front."

The McKelvey School of Engineering at Washington University in St. Louis focuses intellectual efforts through a new convergence paradigm and builds on strengths, particularly as applied to medicine and health, energy and environment, entrepreneurship and security. With 98 tenured/tenure-track and 38 additional full-time faculty, 1,387 undergraduate students, 1,448 graduate students and 20,000 alumni, we are working to leverage our partnerships with academic and industry partners — across disciplines and across the world — to contribute to solving the greatest global challenges of the 21st century.

Mathur J, Sarker B, Pathak A. Predicting collective migration of cell populations defined by varying re-polarization dynamics. Biophysical Journal, published online Nov. 16, 2018. DOI: 10.1016/j.bpj.2018.11.013

Funding for this research was provided by the National Institutes of Health (R35 GM128764).