Metastasis, the spread of cancer cells from primary tumors to distant organs, is responsible for most cancer-related deaths. Yet, only a small fraction of circulating tumor cells survive the journey through the bloodstream and form secondary tumors. The precise mechanisms that enable this survival and transformation remain incompletely understood. This microfluidic study explored whether the physical forces cancer cells experience while squeezing through narrow blood vessels could be a hidden driver of tumor progression.
“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 this question, the researchers developed a custom microfluidic chip that mimics the gradual narrowing of capillaries. The microfluidic chip consisted of parallel microchannels with decreasing diameters down to 5 μm, closely resembling the dimensions of microcapillaries in the body. As melanoma cells traveled through the microfluidic constrictions under physiologically relevant flow rates, they underwent significant deformation of their membranes and nuclei. This deformation led to rapid chromatin remodeling and shifts in histone modifications, indicating changes in gene regulation without causing DNA damage.
RNA sequencing of the “squeezed” cells revealed extensive transcriptional reprogramming, including the activation of genes linked to calcium signaling, angiogenesis, and invasion. Importantly, the mechanosensitive ion channel PIEZO1 was found to play a central role: its activation triggered calcium influx that initiated the reprogramming. Pharmacological inhibition of PIEZO1 blocked the transition, while artificial activation induced it even without constriction.
“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.
In conclusion, this microfluidic work demonstrates that the mechanical stress of navigating capillary-like constrictions can reprogram circulating cancer cells into tumorigenic, stem cell-like states via PIEZO1 activity. Far from being passive obstacles, the physical barriers of the microvasculature can actively shape cancer progression by priming cells for metastasis. This work highlights the possibility of 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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