Working together, cells extend their senses

The story of the princess and the pea evokes an image of a highly sensitive royal young woman so refined, she can sense a pea under stacks of mattresses. When it comes to human biology, it also takes an abnormal individual to sense far beyond its surroundings, in this case, a cancer cell. Now researchers also know that normal cells can pull a similar trick by grouping together.

Research published in the journal PNAS from engineers at Washington University in St. Louis offers a clearer picture of how cells sense beyond their direct environment. The research can help further understanding of how cancer moves and point to potential targets to stop that migration.

Amit Pathak, professor of Mechanical Engineering & Materials Science (MEMS) at the McKelvey School of Engineering explained that “depth mechano-sensing” is how cells sense beyond what they are attached to. In previous research, he and colleagues discovered abnormal cells with a “high front-rear polarity” (indicative of migrating cells) can sense the farthest depth, up 10 microns beyond the adhered environment.

Part of that sensory ability has to do with how the cell deforms the surrounding fibrous collagen to reach out into extracellular matrix (ECM) and “feel” the next layers, whether it’s a hard tumor, soft tissue or bone just around the bend. The single abnormal cell can “feel” the stiffness of the ECM and set its course based on that input.

The new research shows that a collective of epithelial cells (found on the surface of tissue) can do the same and then some, working as one to get enough force to feel through the fibrous collagen what’s at depths up to 100 microns away.

“Because it’s a collective of cells they are generating higher forces,” said Pathak, who authored the research along with Hongsheng Yu, a PhD student in MEMS.

According to their models, this occurs in two distinct phases of cell clustering and migration. Depending on what those clustering cells “feel” it will impact migration and dispersal.

The extra sensing power of cancer cells means that they can get out of the tumor environment and evade detection, migrating freely thanks to their enhanced sense of what’s ahead, even in a soft environment. The next step for the research will be understanding how that works, and if there are certain regulators that allow for the range. Those regulators could be potential targets to hit in cancer therapy. If a cancer cell can’t “feel” its way forward, it’s toxic spread may be put in check. 

Hongsheng Y, Pathak A. Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices. PNAS, Sept 11, 2025.  DOI: https://doi.org/10.1073/pnas.2423875122

Funding for this research was provided by the National Institutes of Health (R35GM128764 National Science Foundation, Civil, Mechanical and Manufacturing Innovation 2209684).

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