Unravelling cell migration: defining movement from the cell surface

Merino-Casallo, Francisco; Gómez‐Benito, María José; Hervas-Raluy, Silvia; Aznar, José Manuel García

doi:10.1080/19336918.2022.2055520

Cited by 42 publications

(37 citation statements)

References 407 publications

(527 reference statements)

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“…Motile cells display a wide range of migratory behaviours [1]. They can bias their direction of locomotion by heading to the source of a stimulus, or randomly explore their surrounding environment [12]. Understanding the underlying mechanisms that lead to different patterns of cell migration (e.g.…”

Section: Introductionmentioning

confidence: 99%

Polarity and mixed-mode oscillations may underlie different patterns of cellular migration

Plazen

Rahbani

Brown

et al. 2022

Preprint

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In mesenchymal cell motility, several migration patterns have been observed, including directional, exploratory and stationary. Two key members of the Rho-family of GTPases, Rac and Rho, along with an adaptor protein called paxillin, have been particularly implicated in the formation of such migration patterns and in regulating adhesion dynamics. Together, they form a key regulatory network that involves the mutual inhibition exerted by Rac and Rho on each other and the promotion of Rac activation by phosphorylated paxillin. Although this interaction is sufficient to generating wave-pinning that underscores cellular polarization comprised of cellular front (high active Rac) and back (high active Rho), it remains unclear how they interact collectively to induce other modes of migration detected in Chinese hamster Ovary (CHO-K1) cells. We previously developed a 6D reaction-diffusion model describing the interactions of these three proteins (in their active/phosphorylated and inactive/unphosphorylated forms) along with other auxiliary proteins, to decipher their role in generating wave-pinning. In this study, we explored, through computational modeling and image analysis, how differences in timescales within this molecular network can potentially produce the migration patterns in CHO-K1 cells and how switching between them could occur. To do so, the 6D model was reduced to an excitable 4D spatiotemporal model possessing three different timescales. The model produced not only wave-pinning in the presence of diffusion, but also mixed-mode oscillations (MMOs) and relaxation oscillations (ROs). Implementing the model using the Cellular Potts Model (CPM) produced outcomes in which protrusions in cell membrane changed Rac-Rho localization, resulting in membrane oscillations and fast directionality variations similar to those seen in CHO-K1 cells. The latter was assessed by comparing the migration patterns of CHO-K1 cells with CPM cells using four metrics: instantaneous cell speed, exponent of mean square-displacement (called α-value), directionality ratio and protrusion rate. Variations in migration patterns induced by mutating paxillin's serine 273 residue was also captured by the model and detected by a machine classifier, revealing that this mutation alters the dynamics of the system from MMOs to ROs or nonoscillatory behaviour through variation in the concentration of an active form of an adhesion protein called p21-Activated Kinase 1 (PAK). These results thus suggest that MMOs and adhesion dynamics are the key ingredients underlying CHO-K1 cell motility.

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Section: Introductionmentioning

confidence: 99%

Polarity and mixed-mode oscillations may underlie different patterns of cellular migration

Plazen

Rahbani

Brown

et al. 2022

Preprint

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“…The increase in collagen fibers could also provide more potential ligands for cells to adhere to and propel through the matrix. We next evaluate this hypothesis by quantifying peripheral cell polarization, which indicates stronger propulsion forces at the spheroid’s boundary [29, 30].…”

Section: Resultsmentioning

confidence: 99%

“…The ability of cells at the leading edge of the spheroid to adhere to surrounding collagen fibers and exert propulsion forces is in part dependent on the ability of cells to polarize [29, 30]. Thus, cell invasion into the surrounding collagen matrix is dependent on cell polarization.…”

Section: Resultsmentioning

confidence: 99%

“…If the cell is elongated (mesenchymal), radial symmetry is lost, and an effective force is generated along the direction of polarization [29, 31]. This effective force does not only depend on cell polarity but also on other features such as the formation of focal adhesions, the stiffness and viscous relaxation of the ECM matrix, and the active stress within the cell [29, 32, 30]. Therefore, the variations introduced in this work at the intercellular and extracellular levels may alter cell polarization, explaining in part the invasion patterns presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Tumor proliferation and invasion are coupled through cell-extracellular matrix friction

Crawford

Gomez-Cruz

Russo

et al. 2022

Preprint

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Cell proliferation and invasion are two key drivers of tumor progression and are traditionally considered two independent cellular processes regulated by distinct pathways. Throughin vitroandin silicomethods, we provide evidence that these two processes are intrinsically coupled through matrix-adhesion friction. Using novel tumor spheroids, we show that both tumor cell proliferation and invasion are limited by a volumetric carrying capacity of the system, i.e. maximum spatial cell concentration supported by the system’s total cell count, nutrient consumption rate, and collagen gel mechanical properties. To manipulate these phenotypes in breast cancer cells, we modulate the expression of E-cadherin and its associated role in adhesion, invasion, and proliferation. We integrate these results into a mixed-constitutive formulation to computationally delineate the contributions of cellular and extracellular adhesion, stiffness, and mechanical properties of the extracellular matrix (ECM) to the proliferative and invasive fates of breast cancer tumor spheroids. Both approaches conclude that the dominant drivers of tumor fate are system properties modulating cell-ECM friction, such as E-cadherin dependent cell-ECM adhesion and matrix pore size.

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“…In addition, ECM is the reservoir and binding site of bioactive molecules. Cell surface receptors transmit signals from the ECM to cells, regulating various cellular functions, including survival, growth, migration, differentiation, and immunity, for maintaining normal homeostasis ( 3 – 5 ). The ECM promotes cancer cell growth, survival, and invasion and modifies fibroblast and immune cell behavior to drive metastasis and impair treatment ( 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

The role of microfibrillar‐associated protein 2 in cancer

Wang

Bai

et al. 2022

Front. Oncol.

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Microfibrillar-associated protein 2 (MFAP2), a component of the extracellular matrix, is important in controlling growth factor signal transduction. Recent studies have shown that MFAP2, an effective prognostic molecule for various tumors, is associated with tumor occurrence and development and may be involved in remodeling the extracellular matrix and regulating proliferation, apoptosis, invasion, tumor cell metastasis, and tumor angiogenesis. However, MFAP2’s specific mechanism in these tumor processes remains unclear. This article reviewed the possible mechanism of MFAP2 in tumorigenesis and progression and provided a reference for the clinical prognosis of patients with cancer and new therapeutic target discovery.

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Unravelling cell migration: defining movement from the cell surface

Cited by 42 publications

References 407 publications

Polarity and mixed-mode oscillations may underlie different patterns of cellular migration

Polarity and mixed-mode oscillations may underlie different patterns of cellular migration

Tumor proliferation and invasion are coupled through cell-extracellular matrix friction

The role of microfibrillar‐associated protein 2 in cancer

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