Macroscopic limit of a kinetic model describing the switch in T cell migration modes via binary interactions

Experimental results on the immune response to cancer indicate that activation of cytotoxic T lymphocytes (CTLs) through interactions with dendritic cells (DCs) can trigger a change in CTL migration patterns. In particular, while CTLs in the pre-activation state move in a non-local search pattern, the search pattern of activated CTLs is more localised. In this paper, we develop a kinetic model for such a switch in CTL migration modes. The model is formulated as a coupled system of balance equations for the one-particle distribution functions of CTLs in the pre-activation state, activated CTLs and DCs. CTL activation is modelled via binary interactions between CTLs in the pre-activation state and DCs. Moreover, cell motion is represented as a velocity-jump process, with the running time of CTLs in the pre-activation state following a long-tailed distribution, which is consistent with a Lévy walk, and the running time of activated CTLs following a Poisson distribution, which corresponds to Brownian motion. We formally show that the macroscopic limit of the model comprises a coupled system of balance equations for the cell densities, whereby activated CTL movement is described via a classical diffusion term, whilst a fractional diffusion term describes the movement of CTLs in the pre-activation state. The modelling approach presented here and its possible generalisations are expected to find applications in the study of the immune response to cancer and in other biological contexts in which switch from non-local to localised migration patterns occurs

Corrosion Behavior of Carbon Steels in CCTS Environment

The paper reports the results of an experimental work on the effect of steel microstructures on morphology and protectiveness of the corrosion scale formed in water saturated by supercritical CO2. Two HSLA steels were tested. The microstructures were modified by means of different heat treatments. Weight loss was measured after exposure at CO2 partial pressure of 80 bar and 60°C temperature. The morphology of the scale was analyzed by means of scanning electron microscope (SEM) energy-dispersive X-ray spectroscopy (EDX). Cathodic potentiodynamic tests were carried out on precorroded specimens for evaluating the effect of preformed scales on cathodic polarization curves in CO2 saturated sulphuric acid solution at pH 3, which is the value estimated for water saturated by supercritical CO2. The results are discussed in order to evaluate the effect of iron carbide network on scale growth and corrosion rate. Weight loss tests evidenced average corrosion rate values in the range 1–2.5 mm/y after 150-hour exposure. The presence of thick siderite scale significantly reduces the corrosion rate of carbon steel. A slight decrease of the corrosion rate was observed as the scale thickness increases and moving from martensite to microstructures containing carbides

A Mathematical Study of the Influence of Hypoxia and Acidity on the Evolutionary Dynamics of Cancer

Hypoxia and acidity act as environmental stressors promoting selection for cancer cells with a more aggressive phenotype. As a result, a deeper theoretical understanding of the spatio-temporal processes that drive the adaptation of tumour cells to hypoxic and acidic microenvironments may open up new avenues of research in oncology and cancer treatment. We present a mathematical model to study the influence of hypoxia and acidity on the evolutionary dynamics of cancer cells in vascularised tumours. The model is formulated as a system of partial integro-differential equations that describe the phenotypic evolution of cancer cells in response to dynamic variations in the spatial distribution of three abiotic factors that are key players in tumour metabolism: oxygen, glucose and lactate. The results of numerical simulations of a calibrated version of the model based on real data recapitulate the eco-evolutionary spatial dynamics of tumour cells and their adaptation to hypoxic and acidic microenvironments. Moreover, such results demonstrate how nonlinear interactions between tumour cells and abiotic factors can lead to the formation of environmental gradients which select for cells with phenotypic characteristics that vary with distance from intra-tumour blood vessels, thus promoting the emergence of intra-tumour phenotypic heterogeneity. Finally, our theoretical findings reconcile the conclusions of earlier studies by showing that the order in which resistance to hypoxia and resistance to acidity arise in tumours depend on the ways in which oxygen and lactate act as environmental stressors in the evolutionary dynamics of cancer cells

On interfaces between cell populations with different mobilities

Partial differential equations describing the dynamics of cell population densities from a fluid mechanical perspective can model the growth of avascular tumours. In this framework, we consider a system of equations that describes the interaction between a population of dividing cells and a population of non-dividing cells. The two cell populations are characterised by different mobilities. We present the results of numerical simulations displaying two-dimensional spherical waves with sharp interfaces between dividing and non-dividing cells. Furthermore, we numerically observe how different ratios between the mobilities change the morphology of the interfaces, and lead to the emergence of finger-like patterns of invasion above a threshold. Motivated by these simulations, we study the existence of one-dimensional travelling wave solutions

Tracking the evolution of cancer cell populations through the mathematical lens of phenotype-structured equations

Background: A thorough understanding of the ecological and evolutionary mechanisms that drive the phenotypic evolution of neoplastic cells is a timely and key challenge for the cancer research community. In this respect, mathematical modelling can complement experimental cancer research by offering alternative means of understanding the results of in vitro and in vivo experiments, and by allowing for a quick and easy exploration of a variety of biological scenarios through in silico studies. Results: To elucidate the roles of phenotypic plasticity and selection pressures in tumour relapse, we present here a phenotype-structured model of evolutionary dynamics in a cancer cell population which is exposed to the action of a cytotoxic drug. The analytical tractability of our model allows us to investigate how the phenotype distribution, the level of phenotypic heterogeneity, and the size of the cell population are shaped by the strength of natural selection, the rate of random epimutations, the intensity of the competition for limited resources between cells, and the drug dose in use. Conclusions: Our analytical results clarify the conditions for the successful adaptation of cancer cells faced with environmental changes. Furthermore, the results of our analyses demonstrate that the same cell population exposed to different concentrations of the same cytotoxic drug can take different evolutionary trajectories, which culminate in the selection of phenotypic variants characterised by different levels of drug tolerance. This suggests that the response of cancer cells to cytotoxic agents is more complex than a simple binary outcome, i.e., extinction of sensitive cells and selection of highly resistant cells. Also, our mathematical results formalise the idea that the use of cytotoxic agents at high doses can act as a double-edged sword by promoting the outgrowth of drug resistant cellular clones. Overall, our theoretical work offers a formal basis for the development of anti-cancer therapeutic protocols that go beyond the 'maximum-tolerated-dose paradigm', as they may be more effective than traditional protocols at keeping the size of cancer cell populations under control while avoiding the expansion of drug tolerant clones. Reviewers: This article was reviewed by Angela Pisco, Sébastien Benzekry and Heiko Enderling

From individual-based mechanical models of multicellular systems to free-boundary problems

In this paper we present an individual-based mechanical model that describes the dynamics of two contiguous cell populations with different proliferative and mechanical characteristics. An off-lattice modelling approach is considered whereby: (i) every cell is identified by the position of its centre; (ii) mechanical interactions between cells are described via generic nonlinear force laws; and (iii) cell proliferation is contact inhibited. We formally show that the continuum counterpart of this discrete model is given by a free-boundary problem for the cell densities. The results of the derivation demonstrate how the parameters of continuum mechanical models of multicellular systems can be related to biophysical cell properties. We prove an existence result for the free-boundary problem and construct travelling-wave solutions. Numerical simulations are performed in the case where the cellular interaction forces are described by the celebrated Johnson-Kendalli-Roberts model of elastic contact, which has been previously used to model cell-cell interactions. The results obtained indicate excellent agreement between the simulation results for the individual-based model, the numerical solutions of the corresponding free-boundary problem and the travelling-wave analysis

Effects of an advection term in nonlocal lotka-volterra equations

Nonlocal Lotka-Volterra equations have the property that solutions concentrate as Dirac masses in the limit of small diffusion. In this paper, we show how the presence of an advection term changes the location of the concentration points in the limit of small diffusion and slow drift. The mathematical interest lies in the formalism of constrained Hamilton-Jacobi equations. Our motivations come from previous models of evolutionary dynamics in phenotype-structured populations [R.H. Chisholm, T. Lorenzi, A. Lorz, et al., Cancer Res., 75, 930-939, 2015], where the diffusion operator models the effects of heritable variations in gene expression, while the advection term models the effect of stress-induced adaptation

Cell population heterogeneity and evolution towards drug resistance in cancer: Biological and mathematical assessment, theoretical treatment optimisation

Background Drug-induced drug resistance in cancer has been attributed to diverse biological mechanisms at the individual cell or cell population scale, relying on stochastically or epigenetically varying expression of phenotypes at the single cell level, and on the adaptability of tumours at the cell population level. Scope of review We focus on intra-tumour heterogeneity, namely between-cell variability within cancer cell populations, to account for drug resistance. To shed light on such heterogeneity, we review evolutionary mechanisms that encompass the great evolution that has designed multicellular organisms, as well as smaller windows of evolution on the time scale of human disease. We also present mathematical models used to predict drug resistance in cancer and optimal control methods that can circumvent it in combined therapeutic strategies. Major conclusions Plasticity in cancer cells, i.e., partial reversal to a stem-like status in individual cells and resulting adaptability of cancer cell populations, may be viewed as backward evolution making cancer cell populations resistant to drug insult. This reversible plasticity is captured by mathematical models that incorporate between-cell heterogeneity through continuous phenotypic variables. Such models have the benefit of being compatible with optimal control methods for the design of optimised therapeutic protocols involving combinations of cytotoxic and cytostatic treatments with epigenetic drugs and immunotherapies. General significance Gathering knowledge from cancer and evolutionary biology with physiologically based mathematical models of cell population dynamics should provide oncologists with a rationale to design optimised therapeutic strategies to circumvent drug resistance, that still remains a major pitfall of cancer therapeutics. This article is part of a Special Issue entitled “System Genetics” Guest Editor: Dr. Yudong Cai and Dr. Tao Huang

From a discrete model of chemotaxis with volume-filling to a generalized Patlak–Keller–Segel model

We present a discrete model of chemotaxis whereby cells responding to a chemoattractant are seen as individual agents whose movement is described through a set of rules that result in a biased random walk. In order to take into account possible alterations in cellular motility observed at high cell densities (i.e. volume-filling), we let the probabilities of cell movement be modulated by a decaying function of the cell density. We formally show that a general form of the celebrated Patlak–Keller–Segel (PKS) model of chemotaxis can be formally derived as the appropriate continuum limit of this discrete model. The family of steady-state solutions of such a generalized PKS model are characterized and the conditions for the emergence of spatial patterns are studied via linear stability analysis. Moreover, we carry out a systematic quantitative comparison between numerical simulations of the discrete model and numerical solutions of the corresponding PKS model, both in one and in two spatial dimensions. The results obtained indicate that there is excellent quantitative agreement between the spatial patterns produced by the two models. Finally, we numerically show that the outcomes of the two models faithfully replicate those of the classical PKS model in a suitable asymptotic regime

Modeling the emergence of phenotypic heterogeneity in vascularized tumors

We present a mathematical study of the emergence of phenotypic heterogeneity in vascularized tumors. Our study is based on formal asymptotic analysis and numerical simulations of a system of nonlocal parabolic equations that describes the phenotypic evolution of tumor cells and their nonlinear dynamic interactions with the oxygen, which is released from the intratumoral vascular network. Numerical simulations are carried out both in the case of arbitrary distributions of intratumor blood vessels and in the case where the intratumoral vascular network is reconstructed from clinical images obtained using dynamic optical coherence tomography. The results obtained support a more in-depth theoretical understanding of the eco-evolutionary process which underpins the emergence of phenotypic heterogeneity in vascularized tumors. In particular, our results offer a theoretical basis for empirical evidence indicating that the phenotypic properties of cancer cells in vascularized tumors vary with the distance from the blood vessels, and establish a relation between the degree of tumor tissue vascularization and the level of intratumor phenotypic heterogeneity