18 Sep Microfluidic capillary constrictions prime cancer cell tumorigenicity

Posted at 11:56h in Latest Research by Pouriya Bayat

When cancer cells spread through the body, they often have to squeeze through the narrow confines of tiny blood vessels. This mechanical challenge is more than just a physical obstacle: it can actually change the behavior of the cells themselves. In this study, researchers employed microfluidic technology and asked whether these repeated capillary-like constrictions influence the way cancer cells grow and spread. They focused on PIEZO1, a mechanosensitive ion channel that responds to physical forces.

“Here, we report that constriction during microcapillary transit triggers reprogramming of melanoma cells to a tumorigenic cancer stem cell-like state. Using a microfluidic device mimicking physiological flow rates and gradual capillary narrowing, we show that compression through narrow channels causes cell and nuclear deformation, rapid chromatin remodelling and increased calcium ”

To investigate, the team fabricated microfluidic chips with constricted channels designed to mimic the dimensions of capillaries. Cancer cells were flowed through these microchannels repeatedly, forcing them to deform and recover in ways that resemble what happens as they circulate in the bloodstream. After this treatment in the microfluidic chips, the researchers compared these “constricted” cells with control cells that had not experienced the same mechanical stress.

Cells that had been forced through capillary-like constrictions displayed higher levels of tumorigenic potential when introduced into living models. In other words, a purely mechanical experience, being squeezed through the microfluidic channels, left the cells in a state that made them more likely to form tumors later. Importantly, PIEZO1 turned out to be central to this response. When the activity of PIEZO1 was inhibited or the gene was silenced, the heightened tumor-forming ability of the constricted cells was significantly reduced.

“A Device schematic consisting of a series of parallel constrictive channels of 30 µm (i), 20 µm (ii), 10 µm (iii), 5 µm (iv) diameter. B Images of melanoma cells passing through the micro constrictions and relaxation chambers. (C) Quantification of viable cells in control (CTRL) and squeezed (SQZD) groups. The results are expressed as the mean ± SEM from three independent experiments. Statistical significance assessed with two-sided unpaired t-test: p  =  0.003 (***), 95% CI: [−38.52, −23.48]. D–F Plot of deformation index (DI) of melanoma cells transiting the microfluidic device, demonstration of inverse relationship between channel diameter and median deformation, and quantification of the % median deformation. n = 20 cells for each plotted condition. The observed trend was confirmed with 3x biological repeat experiments performed on different days.” Reproduced from Silvani, G., Kopecky, C., Romanazzo, S. et al. Capillary constrictions prime cancer cell tumorigenicity through PIEZO1. Nat Commun 16, 8160 (2025) under Attribution 4.0 International License.

This microfluidic study also uncovered changes at the cellular and molecular levels. Constricted cells showed altered patterns of gene expression, particularly in pathways linked to cell survival and growth. Their mechanical memory seemed to persist, making them behave differently long after they had passed through the microfluidic capillary-like channels. These findings suggest that physical stresses encountered in the circulation can “reprogram” cancer cells in ways that contribute to disease progression.

Beyond the laboratory, the implications are wide-ranging. Cancer metastasis, the spread of tumors to new sites, is the main cause of cancer-related deaths. Understanding that capillary transit is not just a hurdle but a priming step means that mechanics should be considered alongside genetics and signaling when studying metastasis. By pinpointing PIEZO1 as a key mediator, this research also highlights a potential therapeutic target: if scientists can find safe ways to modulate this mechanosensor, it may be possible to reduce the aggressiveness of circulating tumor cells.

This work underscores the idea that cancer progression is shaped not only by mutations and biochemical cues but also by the physical environment cells encounter. The interplay between mechanics and biology, captured in microfluidic experiments, opens new avenues for both fundamental understanding and clinical translation.

 

Figures are reproduced from Silvani, G., Kopecky, C., Romanazzo, S. et al. Capillary constrictions prime cancer cell tumorigenicity through PIEZO1. Nat Commun 16, 8160 (2025). https://doi.org/10.1038/s41467-025-63374-6 under Creative Commons Attribution 4.0 International License.

 

Read the original article: Capillary constrictions prime cancer cell tumorigenicity through PIEZO1

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