Capillary constrictions prime cancer cell tumorigenicity through PIEZO1
Posted on: 3 August 2025
Preprint posted on 26 July 2025
Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-025-63374-6
Cancer cells that survive, thrive: capillary constrictions as a trigger of mechanotransduction in cancer progression
Selected by Sristilekha NathCategories: bioengineering, cancer biology, cell biology
Background
As cancer cells metastasize from primary sites to distant targets, they encounter diverse biochemical and mechanical environments. Recently, increasing attention has been directed toward understanding how mechanical constraints, such as compressibility, stiffness, and shear stress from surrounding cells, blood vessels, capillaries, and the extracellular matrix (ECM) influence cancer cell states and behaviors during progression. To metastasize successfully, cancer cells must survive and adapt to these physical stresses. In this study, the authors investigate how constrictions imposed by blood capillaries affect and potentiate circulating cancer cells during transit, with a focus on mechanosensitive factors like PIEZO-1. They developed a microfluidic chamber incorporating microchannels of gradually narrowing diameters mimicking the in vivo capillary structures, and pumped cancer cells through it.
Key findings
Cells Undergo Deformation When Encountering Narrow Constrictions
As melanoma cells migrated through the microcapillaries of gradually decreasing diameters intersparsed with spaces allowing transient relaxation, they experienced the greatest membrane and nuclear deformations especially after passing through the narrowest channels. These regions of highest constriction also led to altered chromatin compaction, reflecting potential impact on nuclear organization and chromatin acetylation states.
In vitro and in vivo assays confirm tumorigenicity of constricted cells
Further evaluation of the squeezed cells revealed a distinct transcriptomic profile, with upregulation of genes linked to tumorigenesis, chemoresistance and melanoma cancer stem cell-like states. Additionally, upon injection into mouse models, these squeezed melanoma cells were found to metastasize as observed with IVIS imaging and histological analysis confirming the formation of tumor nodules.
PIEZO-1 as the key mechanosensitive regulator of constriction-induced tumorigenesis
To understand how cells sense and transduce mechanical stimuli during constriction, the authors hypothesized that PIEZO-1, a known mechanosensitive ion channel, might play a key role, consistent with its involvement in cancer-related mechanotransduction. Immunostaining revealed increased PIEZO-1 localization in cells exiting narrow channels, accompanied by elevated calcium activity. Supporting this, pharmacological activation of PIEZO-1 enhanced the expression of cancer stem cell-like markers, while inhibition of ion-gated channels or genetic knockout of PIEZO-1 led to reduced marker expression.
Constriction-induced phenotypes show enhanced interactions with the endothelium
To check the invasiveness of the constricted cells and their interaction with endothelial cells as observed during in vivo cancer progression, the authors conducted a series of assays, including transwell migration, co-culture and chip-based extravasation. These assays revealed cancer-like migratory behavior and reinforced evidence for cancer stem cell-like behavior.
Why I highlight this preprint
As a cell and developmental biology enthusiast, I find it particularly exciting to observe biological processes unfold gradually over time, especially when cells or tissues encounter mechanical constraints that influence their states and behaviors. This study provides a comprehensive overview of cancer cell progression, highlighting how mechanical disturbances experienced by the cells during their journey from primary tumor to metastatic sites might potentiate their progression. I believe the authors raised some important and unique questions about cancer mechanics that could help bridge existing gaps in our understanding of cancer progression in physiological contexts.
Questions for the authors
- Given the observed decrease in CTC viability following microcapillary-like constrictions, what makes the specific subset of cells adapt and survive such mechanical hostilities? What mechanisms or factors do you think contribute to the selection of these resilient cells during this process?
- Is it the inherently acquired cancer cell state over time (maturation) that can aid or elevate the cancer progression or is it driven solely by the mechanical deformation the cells experience?
- The state of stemness appears to be elevated following compressions, as indicated by the upregulation of cancer stem cell-like biomarkers.
- Do you think the cells might exhibit some intermediate states while acquiring these catalyzed behaviors?
- Have you considered examining or have you already looked into cell morphologies during this transition, particularly the cells after the varied microcapillary-like constraint experience?
References
Kamyabi N, Vanapalli SA. Microfluidic cell fragmentation for mechanical phenotyping of cancer cells. Biomicrofluidics. 2016 Mar 15;10(2):021102. doi: 10.1063/1.4944057. PMID: 27042246; PMCID: PMC4798995.
Irianto J, Xia Y, Pfeifer CR, Athirasala A, Ji J, Alvey C, Tewari M, Bennett RR, Harding SM, Liu AJ, Greenberg RA, Discher DE. DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration. Curr Biol. 2017 Jan 23;27(2):210-223. doi: 10.1016/j.cub.2016.11.049. Epub 2016 Dec 15. PMID: 27989676; PMCID: PMC5262636.
Gupta PB, Pastushenko I, Skibinski A, Blanpain C, Kuperwasser C. Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance. Cell Stem Cell. 2019 Jan 3;24(1):65-78. doi: 10.1016/j.stem.2018.11.011. Epub 2018 Dec 13. PMID: 30554963; PMCID: PMC7297507.
doi: https://doi.org/10.1242/prelights.41162
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