arXiv subjects

Milan Milivojevic

Publications and source records attributed to Milan Milivojevic.

9 recordsLinked to original sources

arXiv2026

Active wetting/de-wetting of focal adhesions on viscoelastic substrates

Cell adhesion to viscoelastic substrates is mediated by focal adhesions (FAs), which dynamically couple actomyosin contractility to the extracellular matrix. Although substrate stress relaxation is known to regulate adhesion stability and cell migration, a predictive physical framework linking viscoelasticity to force transmission and adhesion dynamics remains lacking. Here we review briefly what is known about the active wetting and de-wetting of FAs on viscoelastic substrates and synthesize existing experimental and theoretical work into a two-timescale physical framework to describe the phenomena reported. At short timescales, oscillatory actomyosin-driven displacements are transmitted through molecular clutches, leading to frequency-dependent energy transfer to the substrate. We show that this transfer is maximized at an optimal frequency set by a balance between elastic energy storage and viscous dissipation, establishing a resonance-like mechanism that selects both the effective FA stiffness and traction force amplitude. At longer timescales, this mechanically optimal state couples to adhesion remodelling through an effective surface tension, enabling FA growth and disassembly to be interpreted as active wetting and de-wetting processes. The model predicts that adhesion stability and steady-state size are controlled by substrate stiffness and viscoelastic timescales, as well as mechanosensitive feedback mediated by Piezo1-dependent calcium signalling.

cond-mat.soft↗

arXiv2026

A phenomenological multiscale framework for orientational interactions and viscoelasticity in migrating epithelial monolayers

Collective migration of epithelial monolayers emerges from the interplay between mechanical interactions and biochemical signalling. Here, we present a phenomenological mechanobiological framework linking cell-scale orientational interactions to tissue-scale mechanics. We distinguish reversible and irreversible head-on and glancing collisions, showing that reversible interactions store orientational mechanical energy while preserving collision geometry, whereas irreversible interactions dissipate energy and alter cell orientation. The balance between energy storage and dissipation governs collective migration, mechanical feedback, and density-dependent processes including cell jamming and live cell extrusion. These interactions regulate cell elasticity, contractility, and adhesion, thereby modifying epithelial surface tension and the effective viscoelastic response of the monolayer. We quantify these effects using orientational interaction potentials, an effective second virial coefficient, and dimensionless measures of stored and dissipated orientational energy. The relative contribution of these mechanisms increases with cell packing density, becoming dominant near the jamming transition. This framework provides a constitutive interpretation connecting collision-induced orientation dynamics with emergent epithelial rheology and suggests how density-dependent interaction regimes shape collective migration and tissue viscoelasticity.

q-bio.CB↗

arXiv2026

Irregular curvature at focal adhesions modulates Piezo1 activity and low frequency ultrasound induced apoptosis in cancer cells

Low-frequency, low intensity ultrasound (LIUS) has emerged as a promising physical modality capable of inducing selective apoptosis of cancer cells, while sparing healthy epithelial cells and fibroblasts. Hitherto, the mechanism underlying this selectivity has been unclear, but we now propose and develop a theoretical framework linking the distinct mechanical behaviours of cancer versus healthy cells to their differential responses to LIUS. We point out that cancer cells exhibit inhomogeneous ventral stress-fiber networks, which can produce irregular focal adhesion geometry and inward membrane curvature near focal adhesions under low-intensity ultrasound (LIUS). These curvature irregularities can favor loose packing of Piezo1 channels, thereby preserving their activity. In contrast, healthy epithelial cells and fibroblasts display more homogeneous cytoskeletal organization, which can result in more regular curvature profiles adjacent to focal adhesions. This leads to curvature-driven cholesterol redistribution, resulting in altered spatial organization of Piezo1 clusters and reduced coordinated channel activity and allowing cells to remain in their active, proliferative state when exposed to LIUS. Based on theoretical modeling and previous experimental findings, we propose that differences in cytoskeletal organization and membrane curvature can contribute to distinct Piezo1 activation patterns between healthy and cancerous cells. Our analysis identifies curvature-mediated Piezo1 redistribution as a potential physical basis for LIUS selectivity and provides a mechanistic foundation for designing ultrasound-based therapies to exploit the intrinsic cytoskeletal vulnerabilities of cancer cells.

q-bio.BM↗

arXiv2026

Marangoni-Driven Redistribution and Activity of Piezo1 Molecules in Epithelial and Cancer Cells

The activity and distribution of Piezo1 molecules, along with the maturity and strength of focal adhesions (FAs), serve as critical factors influencing cell mechanosensing. Notably, migrating epithelial cells and mesenchymal-like cancer cells exhibit significantly different behaviors regarding these elements. In cancer cells, Piezo1 molecules are distributed uniformly, while in epithelial cells, their distribution is heterogeneous. In epithelial cells, Piezo1 molecules tend to group around FAs, a phenomenon that is enhanced by actomyosin contractility. However, a reduction in contractility results in a more uniform distribution of Piezo1 molecules. The expression and activity levels of Piezo1 molecules are markedly higher in cancer cells compared to epithelial cells. The activity of Piezo1 molecules correlates with the intracellular calcium concentration. Despite the extensive experimental studies on the properties of migrating epithelial and mesenchymal-like cancer cells, the physical explanations remain lacking. The primary objective of this theoretical study is to explore: (i) the inhomogeneous distribution of Piezo1 molecules in epithelial cells in relation to the Marangoni effect, (ii) the heightened activity of Piezo1 molecules in cancer cells by specifying the driving force, and (iii) the influence of membrane-mediated interactions among Piezo1 molecules grouped near FAs in epithelial cells on their activity.

q-bio.CB↗

arXiv2023

Cell jamming and unjamming in development: physical aspects

Collective cell migration is essential for a wide range of biological processes such as: morphogenesis, wound healing, and cancer spreading. However, it is well known that migrating epithelial collectives frequently undergo jamming, stay trapped some period of time, and then start migration again. Consequently, only a part of epithelial cells actively contributes to the tissue development. In contrast to epithelial cells, migrating mesenchymal collectives successfully avoid the jamming. It has been confirmed that the epithelial unjamming cannot be treated as the epithelial-to-mesenchymal transition. Some other mechanism is responsible for the epithelial jamming/unjamming. Despite extensive research devoted to study the cell jamming/unjamming, we still do not understand the origin of this phenomenon. The origin is connected to physical factors such as: the cell compressive residual stress accumulation and surface characteristics of migrating (unjamming) and resting (jamming) epithelial clusters which depend primarily on the strength of cell-cell adhesion contacts and cell contractility. The main goal of this theoretical consideration is to clarify these cause-consequence relations.

q-bio.CB↗

arXiv2023

Physics of collective cell migration

Movement of cell clusters along extracellular matrices (ECM) during tissue development, wound healing, and early stage of cancer invasion involve various inter-connected migration modes such as: (1) cell movement within clusters, (2) cluster extension (wetting) and compression (de-wetting), and (3) directional cluster movement. It has become increasingly evident that dilational and volumetric viscoelasticity of cell clusters and their surrounding substrate significantly influence these migration modes through physical parameters such as: cell and matrix surface tensions, interfacial tension between cells and substrate, gradients of surface and interfacial tensions, as well as, the accumulation of cell and matrix residual stresses. Inhomogeneous distribution of cell surface tension along migrating cell cluster can appear as a consequence of different strength of cell-cell adhesion contacts and cell contractility between leader and follower cells. While the directional cell migration caused by the matrix stiffness gradient (i.e. durotaxis) has been widely elaborated, the structural changes of matrix surface caused by cell tractions which lead to the generation of the matrix surface tension gradient has not been considered yet. The main goal of this theoretical consideration is to clarify the roles of various physical parameters in collective cell migration based on the formulating biophysical model. This complex phenomenon is discussed on the model systems such as the movement of cell clusters on the collagen I gel matrix by simultaneously reviewing various experimental data with and without cells.

q-bio.CB↗

arXiv2022

Active wetting of epithelial tissues: modeling considerations

Morphogenesis, tissue regeneration and cancer invasion involve transitions in tissue morphology. These transitions, caused by collective cell migration (CCM), have been interpreted as active wetting/de-wetting transitions. This phenomenon is considered on model system such as wetting of cell aggregate on rigid substrate which includes cell aggregate movement and isotropic/anisotropic spreading of cell monolayer around the aggregate depending on the substrate rigidity and aggregate size. This model system accounts for the transition between 3D epithelial aggregate and 2D cell monolayer as a product of: (1) tissue surface tension, (2) surface tension of substrate matrix, (3) cell-matrix interfacial tension, (4) interfacial tension gradient, (5) viscoelasticity caused by CCM, and (6) viscoelasticity of substrate matrix. These physical parameters depend on the cell contractility and state of cell-cell and cell matrix adhesion contacts, as well as, the stretching/compression of cellular systems caused by CCM. Despite extensive research devoted to study cell wetting, we still do not understand interplay among these physical parameters which induces oscillatory trend of cell rearrangement. This review focuses on these physical parameters in governing the cell rearrangement in the context of epithelial aggregate wetting.de-wetting, and on the modelling approaches aimed at reproducing and understanding these biological systems. In this context, we do not only review previously-published bio-physics models for cell rearrangement caused by CCM, but also propose new extensions of those models in order to point out the interplay between cell-matrix interfacial tension and epithelial viscoelasticity and the role of the interfacial tension gradient in cell spreading.

q-bio.CB↗

arXiv2021

Viscoelasticity and cell swirling motion

Although collective cell migration (CCM) is a highly coordinated and fine-tuned migratory mode, instabilities in the form of cell swirling motion (CSM) often occur. The CSM represents a product of the active turbulence obtained at low Reynolds number which has a feedback impact to various processes such as morphogenesis, wound healing, and cancer invasion. The cause of this phenomenon is related to the viscoelasticity of multicellular systems in the context of cell residual stress accumulation. Particular interest of this work is to: (1) emphasize the roles of cell shear and normal residual stress accumulated during CCM in the appearance of CSM and (2) consider the dynamics of CSM from the standpoint of rheology. Inhomogeneous distribution of the cell residual stress leads to a generation the viscoelastic force which acts to suppress CCM and can induces the system rapid stiffening. This force together with the surface tension force and traction force is responsible for the appearance of the CSM. In this work, a review of existing literature about viscoelasticity caused by CCM is given along with assortment of published experimental findings, in order to invite experimentalists to test given theoretical considerations in multicellular systems.

q-bio.TO↗

arXiv2021

Surface activity of cancer cells: the fusion of two cell aggregates

Although a good comprehension of how cancer cells collectively migrate by following molecular rules which influence the state of cell-cell adhesion contacts has been generated, the impact of collective migration on cellular rearrangement from subcellular to supracellular level remains less understood. Thus, considering collective cell migration (CCM) of cancer mesenchymal cells on one side and healthy epithelial cells on the other during the fusion of two cell aggregates could result in a powerful tool in order to address the contribution of structural changes at subcellular level which influence the cellular rearrangements and help to understand this important, but still controversial topic. While healthy epithelial cells undergo volumetric cell rearrangement driven by the tissue surface tension, which results in a collision of opposite directed velocity front near the contact point between two cell aggregates, mesenchymal cells follow quite different scenario. These cells are capable of reducing the surface tension and undergo surface cell rearrangement. The main goal of this contribution is to discuss the origin of surface activity of cancer cells by accounting for the crosstalk between cell-cell and cell-ECM adhesion contacts influenced by the cell contractility.

q-bio.CB↗