T cells Use Focal Adhesions to Pull Themselves Through Confined Environments

Caillier, Alexia; Oleksyn, David; Fowell, Deborah J.; Miller, Jim; Oakes, Patrick W.

doi:10.1101/2023.10.16.562587

Cited by 4 publications

(3 citation statements)

References 95 publications

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“…Our results indicate that we can push adherent blebby T cells into a highly migratory phenotype by increasing their contractility and fine-tuning their cortical stiffness to intermediate values. This mode of migration is consistent with a recent study that shows that T cells push and pull on the extracellular matrix and require adhesion-based forces to migrate through in vitro systems (120). It is also consistent with another cell migration study, where recruitment of the branched actin nucleator Arp2/3 frequently follows membrane-cortex detachment, depletion of the ERM membrane-cortex linker ezrin and protrusion expansion (92).…”

Section: Rapid Cell Migration Is Potentially Enabled By a Hybrid Bleb...supporting

confidence: 91%

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds

Alonso-Matilla,

Provenzano,

Odde

2023

Preprint

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ABSTRACT— Many cell types, including transformed cells and immune cells, such as T cells, can produce protrusive, blister-like plasma membrane patches initially devoid of F-actin, called blebs. Despite recent progress in understanding the amoeboid-mesenchymal migration phenotype balance, it remains largely unknown how bleb-producing cells mechanically move through complex environments and what factors set their migration speed and directionality. Here, we have developed a hybrid stochastic-mean field biophysical model of bleb-based cell motility to study the potential for adhesion-free bleb-based migration. We find that simulated cells can only inefficiently migrate in the absence of adhesion-based forces, i.e., cell swimming, by producing high-to-low cortical contractility oscillations, where a high cortical contractility phase characterized by multiple bleb nucleation events is followed by an intracellular pressure buildup recovery phase at low cortical tensions, resulting in net cell motion. Our model suggests that bleb-producing cells can employ a hybrid bleb- and adhesion-based migration mechanism for optimum cell motility and identifies conditions for optimality. We find that blebs nucleate in subcellular regions of high cortical tension, low membrane-cortex linker density and high intracellular osmotic pressure. Lower extracellular matrix stiffnesses favor bleb growth, hence bleb-based cell swimming, which stands in contrast to classical mesenchymal/motor-clutch migration, where cell motility generally increases with increasing matrix stiffness. The developed model is expected to help generate design criteria for engineered immune therapies and provides a physical perspective of the potential migratory mechanisms underlying rapid single-cell migration, particularly in the context of bleb-based/amoeboid migration.Significance StatementT-cell based cancer therapies present a promising approach to treating cancer. Solid tumors create a highly immunosuppressive and fibrotic microenvironment that obstructs the infiltration of cytotoxic T cells, thus promoting tumor growth and metastasis. Despite recent progress, there is still a gap in our understanding of the migration mechanisms used by T cells to mechanically move through tissue. Here we determine that while cell shape deformation-based cell swimming is possibly used as a short-term exploratory mechanism, its predicted associatedin vivomigration capabilities are suboptimal. Instead, our findings propose an alternative adhesion-based hybrid migration mechanism for optimal cell motility. This work provides important insights to aid design of cell engineering strategies to enhance migratory capabilities of antitumor immune cells.

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Section: Rapid Cell Migration Is Potentially Enabled By a Hybrid Bleb...supporting

confidence: 91%

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds

Alonso-Matilla,

Provenzano,

Odde

2023

Preprint

View full text Add to dashboard Cite

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“…The interplay between cells and footprint may be relevant in collective cell migration, where leader cells can pave the way for other cells to follow in their traces. This idea has recently been validated in in vitro experiments in which it has been observed that immune Th1 T cells show a preference for following the tracks that other T cells leave on the ECM (54).…”

Section: R a F Tmentioning

confidence: 88%

“…Human bronchial epithelial cells plated under matrigel showed oscillatory motion as they slowly expanded their explored regions by interactively weakening and carving the ECM (53). Similarly, Th1 T cells deposited on polyacrylamide gels, when covered with agarose gel, migrated along a trajectory, expanding it with each pass as they moved back and forth (54). These findings suggest that the migration modes described here are not necessarily unique to our proposed mechanism or the particular experimental setup of (15) but may arise more generally from how cells make their way through modifying and responding to their environment.…”

Section: R a F Tmentioning

confidence: 99%

Deposited footprints let cells switch between confined, oscillatory, and exploratory migration

Ipiña,

d’Alessandro,

Ladoux

et al. 2023

Preprint

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For eukaryotic cells to heal wounds, respond to immune signals, or metastasize, they must migrate, often by adhering to extracellular matrix. Cells may also secrete matrix factors, leaving behind a footprint that influences their crawling. Recent experiments showed that epithelial cells on micropatterned adhesive stripes move persistently in regions they have previously crawled over, where footprints have been formed, but barely advance into unexplored regions, creating an oscillatory migration of increasing amplitude. Here, we explore through mathematical modeling how footprint secretion and cell responses to footprint combine to allow cells to develop oscillation and other complex migratory motions. We simulate cell crawling with a phase field model coupled to a biochemical model of cell polarity, assuming local contact with the secreted footprint activates Rac1, a polarity protein at the front of the cell. Depending on the footprint secretion rate and the response to the footprint, cells on micropatterned lines can display a variety of types of motility, including confined, oscillatory, and persistent motion. On 2D substrates, we predict a transition between cells undergoing circular motion and cells developing a more exploratory phenotype. Our model shows how minor changes in a cell's interaction with its footprint can completely alter exploration, allowing cells to tightly regulate their motion, as well as leading to a wide spectrum of behaviors when secretion or sensing is variable from cell to cell. Consistent with our computational predictions, we find in earlier experimental data evidence of cells undergoing both circular and exploratory motion. Our work proposes a new paradigm for how cells regulate their own motility.

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Deposited footprints let cells switch between confined, oscillatory, and exploratory migration

Perez Ipiña,

d’Alessandro,

Ladoux

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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For eukaryotic cells to heal wounds, respond to immune signals, or metastasize, they must migrate, often by adhering to extracellular matrix (ECM). Cells may also deposit ECM components, leaving behind a footprint that influences their crawling. Recent experiments showed that some epithelial cell lines on micropatterned adhesive stripes move persistently in regions they have previously crawled over, where footprints have been formed, but barely advance into unexplored regions, creating an oscillatory migration of increasing amplitude. Here, we explore through mathematical modeling how footprint deposition and cell responses to footprint combine to allow cells to develop oscillation and other complex migratory motions. We simulate cell crawling with a phase field model coupled to a biochemical model of cell polarity, assuming local contact with the deposited footprint activates Rac1, a protein that establishes the cell’s front. Depending on footprint deposition rate and response to the footprint, cells on micropatterned lines can display many types of motility, including confined, oscillatory, and persistent motion. On two-dimensional (2D) substrates, we predict a transition between cells undergoing circular motion and cells developing an exploratory phenotype. Small quantitative changes in a cell’s interaction with its footprint can completely alter exploration, allowing cells to tightly regulate their motion, leading to different motility phenotypes (confined vs. exploratory) in different cells when deposition or sensing is variable from cell to cell. Consistent with our computational predictions, we find in earlier experimental data evidence of cells undergoing both circular and exploratory motion.

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T cells Use Focal Adhesions to Pull Themselves Through Confined Environments

Cited by 4 publications

References 95 publications

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds

Deposited footprints let cells switch between confined, oscillatory, and exploratory migration

Deposited footprints let cells switch between confined, oscillatory, and exploratory migration

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