arXiv subjects

Tommaso Lorenzi

Publications and source records attributed to Tommaso Lorenzi.

At least 19 recordsLinked to original sources

arXiv2026

Speed and stability of segregated waves in a pressure-based model of heterogeneous cell populations

We consider a minimal pressure-based model of heterogeneous cell populations consisting of proliferative and non-proliferative cells with different mobilities. The model is formulated as a system of reaction--cross--diffusion equations describing the spatio-temporal dynamics of the cell densities. The model is known to admit one-dimensional travelling wave solutions with strictly segregated components: non-proliferative cells occupy a finite region at the leading edge, while proliferative cells remain at the rear. However, the speed, parameter dependence, and stability of these waves remain poorly understood. In this work, we derive an almost explicit variational bound on the wave speed by reformulating the problem as a free-boundary problem for a generalised porous--Fisher equation. The estimates we obtain apply to general pressure laws and growth kinetics, agree closely with the results of numerical simulations, and become sharp in the incompressible limit, where we formally recover a fully explicit characterisation of the wave speed. We then analyse the stability of the waves to show that segregated waves are stable only when non-proliferative cells are more mobile than proliferative cells. Finally, motivated by numerical observations of finger-like protrusions, we investigate the stability of incompressible segregated circular waves through asymptotic shape-perturbation analysis. This yields explicit expressions for the pressure, interface velocity, and growth rates of angular modes, thereby making evident the destabilisation mechanisms that may lead to the emergence of fingering instability. Interestingly, we find that, in contrast with the one-dimensional case, the stability of such circular waves is not determined solely by the relative value of the mobility coefficients, and thus instabilities may arise irrespective of which cell type has the larger mobility.

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arXiv2026

Derivation and quasi-invariant asymptotics of phenotype-structured integro-differential models

Building upon kinetic theory approaches for mass-varying multi-agent systems, we develop a modelling framework for phenotype-structured populations that makes it possible to bridge individual-level mechanisms with population-scale evolutionary dynamics. We start by formulating a stochastic agent-based model, which describes the dynamics of single population members undergoing proliferation, death, and phenotype changes. Then, we formally derive the corresponding mesoscopic model, which consists of an integro-differential equation for the distribution of population members over the space of phenotypes, where phenotype changes are modelled via an integral kernel. Finally, considering a quasi-invariant regime of small but frequent phenotype changes, we rigorously derive a non-local Fokker-Planck-type equation counterpart of this model, wherein phenotype changes are taken into account by an advection-diffusion term. The theoretical results obtained are illustrated through a sample of results of numerical simulations.

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arXiv2026

On a phenotype-structured phase-field model of nutrient-limited tumour growth

Phase-field models of tumour growth have proved useful as theoretical tools to investigate cancer invasion. A key implicit assumption underlying mathematical models of this type which have so far been proposed, though, is that cells in the tumour are identical. This assumption ignores both the fact that cells in the same tumour may express different characteristics to different extents, exhibiting heterogeneous phenotypes, and the fact that cells may undergo phenotypic changes, with their characteristics evolving over time. To address such a limitation, in this paper we incorporate inter-cellular phenotypic heterogeneity and the evolution of cell phenotypes into the phase-field modelling framework. This is achieved by formulating a phenotype-structured phase-field model of nutrient-limited tumour growth. For this model, we first establish a well-posedness result under general assumptions on the model functions, which encompass a wide spectrum of biologically relevant scenarios. We then present a sample of numerical solutions to showcase key features of spatiotemporal and evolutionary cell dynamics predicted by the model. We conclude with a brief overview of modelling and analytical research perspectives.

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arXiv2026

On a phenotype-structured Shigesada--Kawasaki--Teramoto model: Turing instability and pattern selection under fast phenotype switching

The Shigesada-Kawasaki-Teramoto (SKT) model has become a classical modelling framework for studying spatial segregation and cross-diffusion-driven pattern formation in competing populations. This model assumes phenotypic homogeneity, but phenotypic variability persists within any population and can strongly influence both ecological and evolutionary dynamics. In this paper, we present a generalised phenotype-structured formulation of the SKT model that accounts for phenotypic variability. In this formulation, the competing populations are continuously structured across some phenotype state spaces. Population members move and compete in phenotype-dependent ways, and can also switch between different phenotype states. First we show how a form of the classical SKT model, wherein parameters are written in terms of continuous weighted averages of the phenotype-dependent functions of the generalised structured model, with weights given by the phenotype distributions of the two populations, can be obtained in the quasi-invariant regime of fast phenotype switching. Then, still assuming fast phenotype switching and extending classical Turing-like linear and weakly nonlinear analyses, we explore the conditions for the emergence of spatial patterns, identify a Turing-type bifurcation threshold leading to pattern formation, and investigate the nature of such a bifurcation (super- or sub-critical) as well as the stability of the patterned state. The results obtained make it possible to draw connections between phenotype-dependent model functions and the emergence of population-scale aggregate spatial dynamics, showing in particular how phenotype distributions can act as effective control parameters for Turing instability and pattern selection. These findings are complemented by numerical simulations, which validate the formal asymptotics and confirm the predictions of the pattern formation analyses.

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arXiv2025

Phenotype-structuring of non-local kinetic models of cell migration driven by environmental sensing

The capability of cells to form surface extensions to non-locally probe the surrounding environment plays a key role in cell migration. The existing mathematical models for migration of cell populations driven by this non-local form of environmental sensing rely on the simplifying assumption that cells in the population share the same cytoskeletal properties, and thus form surface extensions of the same size. To overcome this simplification, we develop a kinetic modelling framework wherein a population of migrating cells is structured by a continuous phenotypic variable that captures variability in structural properties of the cytoskeleton. This framework provides a multiscale representation of cell migration, from single-cell dynamics to population-level behaviours, as we start with a microscopic model that describes the dynamics of single cells in terms of stochastic processes. Next, we formally derive the mesoscopic counterpart of this model, which consists of a phenotype-structured kinetic equation that features a phenotype-dependent non-locality. Then, considering an appropriately rescaled version of this kinetic equation, we formally derive the corresponding macroscopic model, which takes the form of a partial differential equation for the cell number density. To validate the formal procedures employed to derive the macroscopic model from the microscopic model, through the mesoscopic one, we first compare the results of numerical simulations of the two models. We then compare numerical solutions of the macroscopic model with the results of cell locomotion assays, to test the ability of the model to recapitulate qualitative features of experimental observations.

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arXiv2025

Kinetic and mean-field modeling of muscular dystrophies

We present a new class of models for assessing the cell dynamics characterising muscular dystrophies. The proposed approach comprises a system of integro-differential equations for the statistical distributions, over a large patient cohort, of the densities of muscle fibers and immune cells implicated in muscle inflammation, degeneration, and regeneration, which underpin disease development. Considering an appropriately scaled version of this model, we formally derive, as the corresponding mean-field limit, a system of Fokker-Planck equations, from which we subsequently derive, as a macroscopic model counterpart, a system of differential equations for the mean densities of muscle and immune cells in the cohort of patients and the related variances. Then, we study long-time asymptotics for the mean-field model by determining the quasi-equilibrium cell distribution functions, which are in the form of probability density functions of inverse Gamma distributions, and proving the long-time convergence to such quasi-equilibrium distributions. The analytical results obtained are illustrated by means of a sample of results of numerical simulations. The modeling approach presented here has the potential to offer new insights into the balance between degeneration and regeneration mechanisms in the progression of muscular dystrophies, and provides a basis for future extensions, including the modeling of therapeutic interventions.

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arXiv2025

A phenotype-structured reaction-diffusion model of avascular glioma growth

We consider a phenotype-structured reaction-diffusion model of avascular glioma growth. The model describes the interaction dynamics between tumour cells and oxygen, and takes into account anisotropic cell movement and oxygen diffusion related to structural anisotropy of the brain's extracellular environment. In this model, phenotypic heterogeneity of tumour cells is captured by a continuous phenotype-structuring variable, the value of which evolves due to phenotypic changes. We first analyse a one-dimensional version of the model and formally show, through a Hopf-Cole transformation, that it admits, in appropriate asymptotic regimes, phenotypically heterogeneous travelling wave solutions, wherein the locally prevailing cell phenotype varies across the wave due to the presence of oxygen gradients. This provides a mathematical formalisation for the emergence of intratumour phenotypic heterogeneity driven by differences in oxygen availability across the tumour. We then report on the results of both 1D simulations, which corroborate the results of formal asymptotic analyses, and 2D simulations, which also demonstrate the impact of anisotropy in cell movement and oxygen diffusion on tumour growth and on the phenotypic composition of the tumour edge. These results are complemented with additional results of 3D simulations, which are carried out on the geometry of the brain by using a hybrid finite difference-finite element method and integrating patient-specific magnetic resonance imaging data with diffusion tensor imaging data.

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arXiv2025

Heterogeneously structured compartmental models of epidemiological systems: from individual-level processes to population-scale dynamics

We develop a general modelling framework for compartmental epidemiological systems structured by continuous variables which are linked to the levels of expression of compartment-specific traits. We start by formulating an individual-based model that describes the dynamics of single individuals in terms of stochastic processes. Then we formally derive: (i) the mesoscopic counterpart of this model, which is formulated as a system of integro-differential equations for the distributions of individuals over the structuring-variable domains of the different compartments; (ii) the corresponding macroscopic model, which takes the form of a system of ordinary differential equations for the fractions of individuals in the different compartments and the mean levels of expression of the traits represented by the structuring variables. We employ a reduced version of the macroscopic model to obtain a general formula for the basic reproduction number, $\mathcal{R}_0$, in terms of key parameters and functions of the underlying microscopic model, so as to illustrate how such a modelling framework makes it possible to draw connections between fundamental individual-level processes and population-scale dynamics. Finally we apply the modelling framework to case studies based on classical compartmental epidemiological systems, for each of which we report on Monte Carlo simulations of the individual-based model as well as on analytical results and numerical solutions of the macroscopic model.

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arXiv2025

Pattern formation within phenotype-structured chemotactic populations

Populations can become spatially organised through chemotaxis autoattraction, wherein population members release their own chemoattractant. Standard models of this process usually assume phenotypic homogeneity, but recent studies have shed illumination on the inherent heterogeneity within populations: in terms of chemotactic behaviour, trait heterogeneity can range from the sensitivity to attractant gradients to the rate at which attractants are produced. We propose a framework that accounts for this heterogeneity, extending the standard Keller-Segel model to a non-local formulation in which the population is continuously structured across some phenotype state space. Focussing on autoattraction, we allow both the chemotactic sensitivity and the rate of attractant secretion to vary across the population and suppose members can switch between different phenotype states. We extend classical Turing-type linear stability analyses to determine the impact of phenotypic structuring on pattern formation, showing that the rate of switching influences both the critical condition for self-organisation and subsequent pattern dynamics. Scenarios in which the chemotactic sensitivity and attractant secretion are positively or negatively correlated are used to highlight the significance of these results.

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arXiv2025

First explore, then settle: a theoretical analysis of evolvability as a driver of adaptation

Evolvability is defined as the ability of a population to generate heritable variation to facilitate its adaptation to new environments or selection pressures. In this article, we consider evolvability as a phenotypic trait subject to evolution and discuss its implications in the adaptation of populations of asexual individuals. We explore the evolutionary dynamics of an actively proliferating population of individuals, subject to changes in their proliferative potential and their evolvability, through mathematical simulations of a stochastic individual-based model and its deterministic continuum counterpart. We find robust adaptive trajectories that rely on individuals with high evolvability rapidly exploring the phenotypic landscape and reaching the proliferative potential with the highest fitness. The strength of selection on the proliferative potential, and the cost associated with evolvability, can alter these trajectories such that, if both are sufficiently constraining, highly evolvable populations can become extinct in our individual-based model simulations. We explore the impact of this interaction at various scales, discussing its effects in undisturbed environments and also in disrupted contexts, such as cancer.

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arXiv2025

Phenotype structuring in collective cell migration:a tutorial of mathematical models and methods

Populations are heterogeneous, deviating in numerous ways. Phenotypic diversity refers to the range of traits or characteristics across a population, where for cells this could be the levels of signalling, movement and growth activity, etc. Clearly, the phenotypic distribution -- and how this changes over time and space -- could be a major determinant of population-level dynamics. For instance, across a cancerous population, variations in movement, growth, and ability to evade death may determine its growth trajectory and response to therapy. In this review, we discuss how classical partial differential equation (PDE) approaches for modelling cellular systems and collective cell migration can be extended to include phenotypic structuring. The resulting non-local models -- which we refer to as phenotype-structured partial integro-differential equations (PS-PIDEs) -- form a sophisticated class of models with rich dynamics. We set the scene through a brief history of structured population modelling, and then review the extension of several classic movement models -- including the Fisher-KPP and Keller-Segel equations -- into a PS-PIDE form. We proceed with a tutorial-style section on derivation, analysis, and simulation techniques. First, we show a method to formally derive these models from underlying agent-based models. Second, we recount travelling waves in PDE models of spatial spread dynamics and concentration phenomena in non-local PDE models of evolutionary dynamics, and combine the two to deduce phenotypic structuring across travelling waves in PS-PIDE models. Third, we discuss numerical methods to simulate PS-PIDEs, illustrating with a simple scheme based on the method of lines and noting the finer points of consideration. We conclude with a discussion of future modelling and mathematical challenges.

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arXiv2025

Spatial segregation across travelling fronts in individual-based and continuum models for the growth of heterogeneous cell populations

We consider a partial differential equation model for the growth of heterogeneous cell populations subdivided into multiple distinct discrete phenotypes. In this model, cells preferentially move towards regions where they feel less compressed, and thus their movement occurs down the gradient of the cellular pressure, which is defined as a weighted sum of the densities (i.e. the volume fractions) of cells with different phenotypes. To translate into mathematical terms the idea that cells with distinct phenotypes have different morphological and mechanical properties, both the cell mobility and the weighted amount the cells contribute to the cellular pressure vary with their phenotype. We formally derive this model as the continuum limit of an on-lattice individual-based model, where cells are represented as single agents undergoing a branching biased random walk corresponding to phenotype-dependent and pressure-regulated cell division, death, and movement. Then, we study travelling wave solutions whereby cells with different phenotypes are spatially segregated across the invading front. Finally, we report on numerical simulations of the two models, demonstrating excellent agreement between them and the travelling wave analysis. The results presented here indicate that inter-cellular variability in mobility can provide the substrate for the emergence of spatial segregation across invading cell fronts.

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arXiv2025

Trait-structured chemotaxis: Exploring ligand-receptor dynamics and travelling wave properties in a Keller-Segel model

A novel trait-structured Keller-Segel model that explores the dynamics of a migrating cell population guided by chemotaxis in response to an external ligand concentration is derived and analysed. Unlike traditional Keller-Segel models, this framework introduces an explicit representation of ligand-receptor bindings on the cell membrane, where the percentage of occupied receptors constitutes the trait that influences cellular phenotype. The model posits that the cell's phenotypic state directly modulates its capacity for chemotaxis and proliferation, governed by a trade-off due to a finite energy budget: cells highly proficient in chemotaxis exhibit lower proliferation rates, while more proliferative cells show diminished chemotactic abilities. The model is derived from the principles of a biased random walk, resulting in a system of two non-local partial differential equations, describing the densities of both cells and ligands. Using a Hopf-Cole transformation, we derive an equation that characterises the distribution of cellular traits within travelling wave solutions for the total cell density, allowing us to uncover the monotonicity properties of these waves. Numerical investigations are conducted to examine the model's behaviour across various biological scenarios, providing insights into the complex interplay between chemotaxis, proliferation, and phenotypic diversity in migrating cell populations.

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arXiv2024

Phenotypic switching mechanisms determine the structure of cell migration into extracellular matrix under the `go-or-grow' hypothesis

A fundamental feature of collective cell migration is phenotypic heterogeneity which, for example, influences tumour progression and relapse. While current mathematical models often consider discrete phenotypic structuring of the cell population, in-line with the `go-or-grow' hypothesis \cite{hatzikirou2012go, stepien2018traveling}, they regularly overlook the role that the environment may play in determining the cells' phenotype during migration. Comparing a previously studied volume-filling model for a homogeneous population of generalist cells that can proliferate, move and degrade extracellular matrix (ECM) \cite{crossley2023travelling} to a novel model for a heterogeneous population comprising two distinct sub-populations of specialist cells that can either move and degrade ECM or proliferate, this study explores how different hypothetical phenotypic switching mechanisms affect the speed and structure of the invading cell populations. Through a continuum model derived from its individual-based counterpart, insights into the influence of the ECM and the impact of phenotypic switching on migrating cell populations emerge. Notably, specialist cell populations that cannot switch phenotype show reduced invasiveness compared to generalist cell populations, while implementing different forms of switching significantly alters the structure of migrating cell fronts. This key result suggests that the structure of an invading cell population could be used to infer the underlying mechanisms governing phenotypic switching.

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arXiv2024

Modelling coevolutionary dynamics in heterogeneous SI epidemiological systems across scales

We develop a new structured compartmental model for the coevolutionary dynamics between susceptible and infectious individuals in heterogeneous SI epidemiological systems. In this model, the susceptible compartment is structured by a continuous variable that represents the level of resistance to infection of susceptible individuals, while the infectious compartment is structured by a continuous variable that represents the viral load of infectious individuals. We first formulate an individual-based model wherein the dynamics of single individuals is described through stochastic processes, which permits a fine-grain representation of individual dynamics and captures stochastic variability in evolutionary trajectories amongst individuals. Next we formally derive the mesoscopic counterpart of this model, which consists of a system of coupled integro-differential equations for the population density functions of susceptible and infectious individuals. Then we consider an appropriately rescaled version of this system and we carry out formal asymptotic analysis to derive the corresponding macroscopic model, which comprises a system of coupled ordinary differential equations for the proportions of susceptible and infectious individuals, the mean level of resistance to infection of susceptible individuals, and the mean viral load of infectious individuals. Overall, this leads to a coherent mathematical representation of the coevolutionary dynamics between susceptible and infectious individuals across scales. We provide well-posedness results for the mesoscopic and macroscopic models, and we show that there is excellent agreement between analytical results on the long-time behaviour of the components of the solution to the macroscopic model, the results of Monte Carlo simulations of the individual-based model, and numerical solutions of the macroscopic model.

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arXiv2024

An individual-based model to explore the impact of psychological stress on immune infiltration into tumour spheroids

In recent in vitro experiments on co-culture between breast tumour spheroids and activated immune cells, it was observed that the introduction of the stress hormone cortisol resulted in a decreased immune cell infiltration into the spheroids. Moreover, the presence of cortisol deregulated the normal levels of the pro- and anti-inflammatory cytokines IFN-γ and IL-10. We present an individual-based model to explore the interaction dynamics between tumour and immune cells under psychological stress conditions. With our model, we explore the processes underlying the emergence of different levels of immune infiltration, with particular focus on the biological mechanisms regulated by IFN-γ and IL-10. The set-up of numerical simulations is defined to mimic the scenarios considered in the experimental study. Similarly to the experimental quantitative analysis, we compute a score that quantifies the level of immune cell infiltration into the tumour. The results of numerical simulations indicate that the motility of immune cells, their capability to infiltrate through tumour cells, their growth rate and the interplay between these cell parameters can affect the level of immune cell infiltration in different ways. Ultimately, numerical simulations of this model support a deeper understanding of the impact of biological stress-induced mechanisms on immune infiltration.

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arXiv2024

Derivation and travelling wave analysis of phenotype-structured haptotaxis models of cancer invasion

We formulate haptotaxis models of cancer invasion wherein the infiltrating cancer cells can occupy a spectrum of states in phenotype space, ranging from `fully mesenchymal' to `fully epithelial'. The more mesenchymal cells are those that display stronger haptotaxis responses and have greater capacity to modify the extracellular matrix (ECM) through enhanced secretion of matrix-degrading enzymes (MDEs). However, as a trade-off, they have lower proliferative capacity than the more epithelial cells. The framework is multiscale in that we start with an individual-based model that tracks the dynamics of single cells, which is based on a branching random walk over a lattice representing both physical and phenotype space. We formally derive the corresponding continuum model, which takes the form of a coupled system comprising a partial integro-differential equation for the local cell population density function, a partial differential equation for the MDE concentration and an infinite-dimensional ordinary differential equation for the ECM density. Despite the intricacy of the model, we show, through formal asymptotic techniques, that for certain parameter regimes it is possible to carry out a detailed travelling wave analysis and obtain invading fronts with spatial structuring of phenotypes. Precisely, the most mesenchymal cells dominate the leading edge of the invasion wave and the most epithelial (and most proliferative) dominate the rear, representing a bulk tumour population. As such, the model recapitulates similar observations into a front to back structuring of invasion waves into leader-type and follower-type cells, witnessed in an increasing number of experimental studies over recent years.

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arXiv2024

Evolutionary dynamics of glucose-deprived cancer cells: insights from experimentally-informed mathematical modelling

Glucose is a primary energy source for cancer cells. Several lines of evidence support the idea that monocarboxylate transporters, such as MCT1, elicit metabolic reprogramming of cancer cells in glucose-poor environments, allowing them to reuse lactate, a byproduct of glucose metabolism, as an alternative energy source with serious consequences for disease progression. We employ a synergistic experimental and mathematical modelling approach to explore the evolutionary processes at the root of cancer cell adaptation to glucose deprivation, with particular focus on the mechanisms underlying the increase in MCT1 expression observed in glucose-deprived aggressive cancer cells. Data from in vitro experiments on breast cancer cells are used to inform and calibrate a mathematical model that comprises a partial integro-differential equation for the dynamics of a population of cancer cells structured by the level of MCT1 expression. Analytical and numerical results of this model suggest that environment-induced changes in MCT1 expression mediated by lactate-associated signalling pathways enable a prompt adaptive response of glucose-deprived cancer cells, whilst fluctuations in MCT1 expression due to epigenetic changes create the substrate for environmental selection to act upon, speeding up the selective sweep underlying cancer cell adaptation to glucose deprivation, and may constitute a long-term bet-hedging mechanism.

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