Mechanical polarity links adhesion-regulated protrusions to directional stability in glioblastoma cell migration
- 1Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Japan
- 2Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka, Japan
- 3Data Science Center, Nara Institute of Science and Technology, Ikoma, Japan
Abstract
Glioblastoma invasion critically limits therapeutic outcomes, yet the physical principles that govern directional cell migration remain poorly understood. In particular, the degree to which protrusive forces are aligned or cancel each other, and how this governs migration efficiency, have remained unquantified. Here, we introduce mechanical polarity, a quantitative descriptor that captures the alignment of protrusive and adhesive forces driving migration. By integrating time-lapse imaging of the glioblastoma-derived cells with a coarse-grained biophysical model incorporating catch- and slip-bond kinetics, we analyzed motility on fibronectin- and laminin-coated substrates. In our model, the extracellular matrix (ECM) is treated as an external boundary condition that modulates adhesion dynamics, distinct from intrinsic cellular mechanics. We demonstrate that while protrusive activity remains similar across environments, the fibronectin-fitted model exhibited less stable effective adhesion dynamics that led to poorly coordinated protrusions and significant force cancellation, thereby reducing net displacement. These differences are not fully captured by conventional descriptors of protrusion activity but are reflected in mechanical polarity. Conversely, laminin promotes stable adhesions and the alignment of protrusive forces, a state characterized by high mechanical polarity. Our results support mechanical polarity as a candidate physical descriptor linking molecular adhesion kinetics to cell-scale migration stability. This framework provides a quantitative basis for understanding force coordination in glioblastoma cell motility and offers a physical basis for strategies to suppress invasive behavior. Author summary: Glioblastoma is an aggressive brain cancer characterized by its ability to infiltrate healthy brain tissue, making complete surgical removal nearly impossible. While it is known that cancer cells move by generating mechanical forces, it has remained unclear how the many small, fluctuating forces produced by cellular protrusions are coordinated to generate stable, directional motion. In this study, we introduce mechanical polarity, a simple measure that quantifies how well these forces are aligned. By combining real-time imaging of patient-derived cancer cells with mathematical modeling, we show that cells can exhibit similar levels of protrusive activity yet move very differently depending on their environment. On some substrates, unstable adhesions cause forces to oppose each other, effectively canceling movement and leading to inefficient, wandering behavior. On others, stable adhesions promote force alignment, enabling efficient and persistent migration. Importantly, these differences are not directly explained by conventional descriptors based on cell shape or activity, but are revealed by mechanical polarity. Our findings provide a new physical framework for understanding how cells organize forces to move and suggest new strategies for limiting invasive behavior by disrupting force coordination.
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BibTeX
@article{tagawa2026mechanical,
title = {{Mechanical polarity links adhesion-regulated protrusions to directional stability in glioblastoma cell migration}},
author = {Haruna Tagawa and Daisuke Kanematsu and Asako Katsuma and Naoyuki Inagaki and Yonehiro Kanemura and Yuichi Sakumura},
journal = {PLOS Computational Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pcbi.1014772},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014772},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanical polarity links adhesion-regulated protrusions to directional stability in glioblastoma cell migration
AU - Haruna Tagawa
AU - Daisuke Kanematsu
AU - Asako Katsuma
AU - Naoyuki Inagaki
AU - Yonehiro Kanemura
AU - Yuichi Sakumura
PY - 2026
DA - 2026/09/24
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014772
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014772
AB - Glioblastoma invasion critically limits therapeutic outcomes, yet the physical principles that govern directional cell migration remain poorly understood. In particular, the degree to which protrusive forces are aligned or cancel each other, and how this governs migration efficiency, have remained unquantified. Here, we introduce mechanical polarity, a quantitative descriptor that captures the alignment of protrusive and adhesive forces driving migration. By integrating time-lapse imaging of the glioblastoma-derived cells with a coarse-grained biophysical model incorporating catch- and slip-bond kinetics, we analyzed motility on fibronectin- and laminin-coated substrates. In our model, the extracellular matrix (ECM) is treated as an external boundary condition that modulates adhesion dynamics, distinct from intrinsic cellular mechanics. We demonstrate that while protrusive activity remains similar across environments, the fibronectin-fitted model exhibited less stable effective adhesion dynamics that led to poorly coordinated protrusions and significant force cancellation, thereby reducing net displacement. These differences are not fully captured by conventional descriptors of protrusion activity but are reflected in mechanical polarity. Conversely, laminin promotes stable adhesions and the alignment of protrusive forces, a state characterized by high mechanical polarity. Our results support mechanical polarity as a candidate physical descriptor linking molecular adhesion kinetics to cell-scale migration stability. This framework provides a quantitative basis for understanding force coordination in glioblastoma cell motility and offers a physical basis for strategies to suppress invasive behavior. Author summary: Glioblastoma is an aggressive brain cancer characterized by its ability to infiltrate healthy brain tissue, making complete surgical removal nearly impossible. While it is known that cancer cells move by generating mechanical forces, it has remained unclear how the many small, fluctuating forces produced by cellular protrusions are coordinated to generate stable, directional motion. In this study, we introduce mechanical polarity, a simple measure that quantifies how well these forces are aligned. By combining real-time imaging of patient-derived cancer cells with mathematical modeling, we show that cells can exhibit similar levels of protrusive activity yet move very differently depending on their environment. On some substrates, unstable adhesions cause forces to oppose each other, effectively canceling movement and leading to inefficient, wandering behavior. On others, stable adhesions promote force alignment, enabling efficient and persistent migration. Importantly, these differences are not directly explained by conventional descriptors based on cell shape or activity, but are revealed by mechanical polarity. Our findings provide a new physical framework for understanding how cells organize forces to move and suggest new strategies for limiting invasive behavior by disrupting force coordination.
SN - 1553-7358
ER -