“Tug of war” explains diversity of cell migration patterns

Live cells can successfully navigate complex terrains inside intertwined human tissues, showing different migration patterns, sometimes moving apparently at random, sometimes in back-and-forth steps, occasionally switching to what amounts to very persistent directed migration.

Scientists have studied these and other cell locomotion patterns, but until now no single mechanism has been proposed to explain why cells employ diverse migration patterns under the same conditions, with single cells switching between them with what seems like uncanny regularity.

In a recent study in the Proceedings of the National Academy of Sciences USA, Andre Levchenko and members of his lab at Yale’s System’s Biology Institute (SBI) have identified the long-sought mechanism accounting for all the diverse cellular migration patterns, choosing them with precisely defined probabilities within the tissue matrix - a bioactive, polymer network gluing the tissues together.

Working in collaboration with researchers from the University of British Columbia, the scientists used a combination of novel nano-fabricated platforms, mathematical modeling and cell biology techniques to discover the elegant fashion by which cells control their movement though a “tug-of-war” interplay between two signaling pathways, each of which is activated by the same biochemical input arising from the tissue matrix itself.

This mechanism, when translated into a mathematical model, can also explain how a cell population splits itself into precise proportions of cells assuming different migration patterns. These proportions can change if cells are treated with a diverse set of drugs or undergo genetic mutations.

The researchers tested the model and its predictions using two versions of human melanoma cells: benign cells and metastatic cells, the latter of which contribute to the active spread of the cancer.

Melanoma is a common skin cancer that can be particularly deadly in advanced stages due to aggressive cell invasion and metastatic spread, frequently leading to fatal outcomes within a year of diagnosis.

The mechanism identified by Levchenko and his team also predicted the effects of multiple drugs on these cells, revealing the pharmacological treatments that switch cells from persistent migration patterns to random, less productive migrations or oscillations.

“Strikingly, the model predicted how the persistence of cell migration changes as the cells switch to invasive spread,” explained Levchenko, Director of Yale’s Systems Biology Institute, and the paper’s senior author. “The mechanism and the mathematical model were also able to explain many previous experimental observations, published for a variety of different cells types, making it likely that the mechanism is valid and universal.”

The likely reason for the palette of different migration patterns available to the cells has to do with the effectiveness of cell spread through complex tissues.

“Cells can ‘choose’ the migration type that best corresponds to the particular biochemical and mechanical environment, so they have the best chance of finding themselves away from the site of departure and close to a target site,” said JinSeok Park, Postdoctoral Associate in Biomedical Engineering at the SBI and primary author of the work.

The theory is being further tested for different cells types in various settings, where it could pave the way to a better understanding of cancer, immune response, development of organisms and other fundamental functions key to healthy and pathological states.

The research is supported by a Samsung scholarship and by grants U54 CA209992 and U01 CA155758 from the National Institutes of Health, among other sources.