Cancer cells exhibit increased motility and proliferation, which are instrumental in the formation of tumours and metastases. These pathological changes can be traced back to malfunctions of cellular signalling pathways, and calcium signalling plays a prominent role in these. We formulate a new model for cancer cell movement which for the first time explicitly accounts for the dependence of cell proliferation and cell-cell adhesion on calcium. At the heart of our work is a non-linear, integro-differential (non-local) equation for cancer cell movement, accounting for cell diffusion, advection and proliferation. We also employ an established model of cellular calcium signalling with a rich dynamical repertoire that includes experimentally observed periodic wave trains and solitary pulses. The cancer cell density exhibits travelling fronts and complex spatial patterns arising from an adhesion-driven instability (ADI). We show how the different calcium signals and variations in the strengths of cell-cell attraction and repulsion shape the emergent cellular aggregation patterns, which are a key component of the metastatic process. Performing a linear stability analysis, we identify parameter regions corresponding to ADI. These regions are confirmed by numerical simulations, which also reveal different types of aggregation patterns and these patterns are significantly affected by \ca. Our study demonstrates that the maximal cell density decreases with calcium concentration, while the frequencies of the calcium oscillations and the cell density oscillations are approximately equal in many cases. Furthermore, as the calcium levels increase the speed of the travelling fronts increases, which is related to a higher cancer invasion potential. These novel insights provide a step forward in the design of new cancer treatments that may rely on controlling the dynamics of cellular calcium.
Cancer cell invasion is recognised as one of the hallmarks of cancer and involves several inner-related multiscale processes that ultimately contribute to its spread into the surrounding tissue. In order to gain a deeper understanding of the tumour invasion process, we pay special attention to the interacting dynamics between the cancer cell population and various constituents of the surrounding tumour microenvironment. To that end, we consider the key role that ECM plays within the human body tissue, providing not only structure and support to surrounding cells, but also acting as a platform …
The migration behaviors of cancer cells are known to be heterogeneous. However, the interplay between the adhesion interactions, dynamical shape changes and fluid flows in regulating cell migration heterogeneity and plasticity during cancer metastasis is still elusive. To further quantitative understanding of cell motility and morphology, we develop a theory using stochastic quantization method that describes the role of biophysical cues in regulating diverse cell motility. We show that the cumulative effect of time dependent adhesion interactions that determine the structural rearrangements a…
Irregular curvature at focal adhesions modulates Piezo1 activity and low frequency ultrasound induced apoptosis in cancer cells
University of Belgrade（贝尔格莱德大学）；Victor Chang Cardiac Research Institute（维克多·陈心脏研究所）；University of New South Wales（新南威尔士大学）；Lancaster University（兰卡斯特大学）
We extend the live-cell motility Filament Based Lamellipodium Model to incorporate the forces exerted on the lamellipodium of the cells due to cell-cell collision and cadherin induced cell-cell adhesion. We take into account the nature of these forces via physical and biological constraints and modelling assumptions. We investigate the effect these new components have in the migration and morphology of the cells through particular experiments. We exhibit moreover the similarities between our simulated cells and HeLa cancer cells.
Cell adhesion, a fundamental process of cell biology is involved in the embryo development and in numerous pathologies especially those related to cancers. We constrained cells to adhere on extracellular matrix proteins patterned in a micro lattices. The actin cytoskeleton is particularly sensitive to this constraint and reproducibly self organizes in simple geometrical patterns. Such highly organized cells are functional and proliferate. We performed statistical analysis of spread cells morphologies and discuss the existence of a fundamental lengthscale associated with active processes requir…
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 influe…
Eukaryotic cell motility is crucial during development, wound healing, the immune response, and cancer metastasis. Some eukaryotic cells can swim, but cells more commonly adhere to and crawl along the extracellular matrix. We study the relationship between hydrodynamics and adhesion that describe whether a cell is swimming, crawling, or combining these motions. Our simple model of a cell, based on the three-sphere swimmer, is capable of both swimming and crawling. As cell-matrix adhesion strength increases, the influence of hydrodynamics on migration diminish. Cells with significant adhesion c…
Current methods for capturing circulating tumor cells (CTCs) are based on the overexpression of cytokeratin (CK) or epithelial cell-adhesion molecule (EpCAM) on cancer cells. However, during the process of metastasis, tumor cells undergo epithelial to mesenchymal transition (EMT) that can lead to the loss of CK/EpCAM expression. Therefore, it is vital to develop a capturing technique independent of CK/EpCAM expression on the cancer cell. To develop this technique, it is important to identify common secondary oncogenic markers overexpressed on tumor cells before and after EMT. We analyzed the b…
Multicellular collective migration is a ubiquitous strategy of cells to translocate spatially in diverse tissue environments to accomplish a wide variety of biological phenomena, viz. embryonic development, wound healing, and tumor progression. Diverse cellular functions and behaviors, for instance, cell protrusions, active contractions, cell-cell adhesion, biochemical signaling, remodeling of tissue micro-environment, etc., play their own role concomitantly to have a single concerted consequence of multicellular migration. Thus unveiling the driving principles, both biochemical and biophysica…
Cell adhesion and migration are strongly influenced by extracellular matrix (ECM) architecture and rigidity, but little is known about the concomitant influence of such environmental signals to cell responses, especially when considering cells of similar origin and morphology, but exhibiting a normal or cancerous phenotype. Using micropatterned polydimethylsiloxane substrates (PDMS) with tuneable stiffness (500kPa, 750kPa, 2000kPa) and topography (lines, pillars or unpatterned), we systematically analyse the differential response of normal (3T3) and cancer (SaI/N) fibroblastic cells. Our resul…
Marangoni-Driven Redistribution and Activity of Piezo1 Molecules in Epithelial and Cancer Cells
University of Belgrade（贝尔格莱德大学）；Victor Chang Cardiac Research Institute（维克多·陈心脏研究所）；University of New South Wales（新南威尔士大学）；Lancaster University（兰开斯特大学）
Metastases are the primary cause of death in cancer patients. Small animal models are helping in dissecting some of key features in the metastatic cascade. Yet, tools for systematically analyze the contribution of blood flow, vascular permeability, inflammation, tissue architecture, and biochemical stimuli are missing. In this work, a microfluidic chip is designed and tested to replicate in vitro key steps in the metastatic cascade. It comprises two channels, resting on the same plane, connected via an array of rounded pillars to form a permeable micro-membrane. One channel acts as a vascular …
We provide a review of recent advancements in nonlocal continuous models for migration, mainly from the perspective of its involvement in embryonal development and cancer invasion. Particular emphasis is placed on spatial nonlocality occurring in advection terms, used to characterise a cell's motility bias according to its interactions with other cellular and acellular components in its vicinity (e.g., cell-cell and cell-tissue adhesions, nonlocal chemotaxis), but we also shortly address spatially nonlocal source terms. Following a brief introduction and motivation, we give a systematic classi…
Collective sensing by interacting cells is observed in a variety of biological systems, and yet a quantitative understanding of how sensory information is collectively encoded is lacking. Here we investigate the ATP-induced calcium dynamics of monolayers of fibroblast cells that communicate via gap junctions. Combining experiments and stochastic modeling, we find that increasing the ATP stimulus increases the propensity for calcium oscillations despite large cell-to-cell variability. The model further predicts that the oscillation propensity increases not only with the stimulus, but also with …
Understanding cell-fate decisions during tumorigenesis and metastasis is a major challenge in modern cancer biology. One canonical cell-fate decision that cancer cells undergo is Epithelial-to-Mesenchymal Transition (EMT) and its reverse Mesenchymal-to-Epithelial Transition (MET). While transitioning between these two phenotypes - epithelial and mesenchymal - cells can also attain a hybrid epithelial/mesenchymal (i.e. partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g. adhesion) and mesenchymal (e.g. migration) properties, thereby allowing them to move c…
Cell migration in fibreous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response and cancer progression. During migration, individual cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers through focal adhesion complexes, remodel the ECM, and eventually propagate to and can be sensed by other cells in the system. The microstructure and physical properties of the ECM can also significantly influence cell migration, e.g., via durotaxis and contact guidance. Her…
Tumor invasion, the process by which tumor cells break away from their primary tumor and gain access to vascular systems, is an important step in cancer metastasis. Most current 3D tumor invasion assays consisted of single tumor cells embedded within an extracellular matrix (ECM). These assays taught us much of what we know today on how key biophysical (e.g. ECM stiffness) and biochemical (e.g. cytokine gradients) parameters within the tumor microenvironment guided and regulated tumor invasion. One limitation of the single tumor cell invasion assay was that it did not account for cell-cell adh…
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 be…
There are numerous scenarios in which populations of cells migrate in crowded environments. Typical examples include wound healing, cancer growth and embryo development. In these crowded environments cells are able to interact with each other in a variety of ways. These include excluded volume interactions, adhesion, repulsion, cell signalling, pushing and pulling. One popular way to understand the behaviour of a group of interacting cells is through an agent-based model (ABM). A typical aim of modellers using such represtations is to elucidate how the microscopic interactions at the cell-leve…
