Invasion front dynamics of interactive populations in environments with barriers.

Invading populations normally comprise different subpopulations that interact while trying to overcome existing barriers against their way to occupy new areas. However, the majority of studies so far only consider single or multiple population invasion into areas where there is no resistance against the invasion. Here, we developed a model to study how cooperative/competitive populations invade in the presence of a physical barrier that should be degraded during the invasion. For one dimensional (1D) environment, we found that a Langevin equation as [Formula: see text] describing invasion front position. We then obtained how [Formula: see text] and [Formula: see text] depend on population interactions and environmental barrier intensity. In two dimensional (2D) environment, for the average interface position movements we found a Langevin equation as [Formula: see text]. Similar to the 1D case, we calculate how [Formula: see text] and [Formula: see text] respond to population interaction and environmental barrier intensity. Finally, the study of invasion front morphology through dynamic scaling analysis showed that growth exponent, [Formula: see text], depends on both population interaction and environmental barrier intensity. Saturated interface width, [Formula: see text], versus width of the 2D environment (L) also exhibits scaling behavior. Our findings show revealed that competition among subpopulations leads to more rough invasion fronts. Considering the wide range of shreds of evidence for clonal diversity in cancer cell populations, our findings suggest that interactions between such diverse populations can potentially participate in the irregularities of tumor border.

Geometrically regulating evolutionary dynamics in biofilms.

The theoretical understanding of evolutionary dynamics in spatially structured populations often relies on nonspatial models. Biofilms are among such populations where a more accurate understanding is of theoretical interest and can reveal new solutions to existing challenges. Here, we studied how the geometry of the environment affects the evolutionary dynamics of expanding populations, using the Eden model. Our results show that fluctuations of subpopulations during range expansion in two- and three-dimensional environments are not Brownian. Furthermore, we found that the substrate's geometry interferes with the evolutionary dynamics of populations that grow upon it. Inspired by these findings, we propose a periodically wedged pattern on surfaces prone to develop biofilms. On such patterned surfaces, natural selection becomes less effective and beneficial mutants would have a harder time establishing. Additionally, this modification accelerates genetic drift and leads to less diverse biofilms. Both interventions are highly desired for biofilms.

Superlinear growth reveals the Allee effect in tumors.

Integrating experimental data into ecological models plays a central role in understanding biological mechanisms that drive tumor progression where such knowledge can be used to develop new therapeutic strategies. While the current studies emphasize the role of competition among tumor cells, they fail to explain recently observed superlinear growth dynamics across human tumors. Here we study tumor growth dynamics by developing a model that incorporates evolutionary dynamics inside tumors with tumor-microenvironment interactions. Our results reveal that tumor cells' ability to manipulate the environment and induce angiogenesis drives superlinear growth-a process compatible with the Allee effect. In light of this understanding, our model suggests that, for high-risk tumors that have a higher growth rate, suppressing angiogenesis can be the appropriate therapeutic intervention.

A mesoscopic simulator to uncover heterogeneity and evolutionary dynamics in tumors.

Increasingly complex in silico modeling approaches offer a way to simultaneously access cancerous processes at different spatio-temporal scales. High-level models, such as those based on partial differential equations, are computationally affordable and allow large tumor sizes and long temporal windows to be studied, but miss the discrete nature of many key underlying cellular processes. Individual-based approaches provide a much more detailed description of tumors, but have difficulties when trying to handle full-sized real cancers. Thus, there exists a trade-off between the integration of macroscopic and microscopic information, now widely available, and the ability to attain clinical tumor sizes. In this paper we put forward a stochastic mesoscopic simulation framework that incorporates key cellular processes during tumor progression while keeping computational costs to a minimum. Our framework captures a physical scale that allows both the incorporation of microscopic information, tracking the spatio-temporal emergence of tumor heterogeneity and the underlying evolutionary dynamics, and the reconstruction of clinically sized tumors from high-resolution medical imaging data, with the additional benefit of low computational cost. We illustrate the functionality of our modeling approach for the case of glioblastoma, a paradigm of tumor heterogeneity that remains extremely challenging in the clinical setting.

Universal scaling laws rule explosive growth in human cancers.

Most physical and other natural systems are complex entities composed of a large number of interacting individual elements. It is a surprising fact that they often obey the so-called scaling laws relating an observable quantity with a measure of the size of the system. Here we describe the discovery of universal superlinear metabolic scaling laws in human cancers. This dependence underpins increasing tumour aggressiveness, due to evolutionary dynamics, which leads to an explosive growth as the disease progresses. We validated this dynamic using longitudinal volumetric data of different histologies from large cohorts of cancer patients. To explain our observations we put forward increasingly-complex biologically-inspired mathematical models that captured the key processes governing tumor growth. Our models predicted that the emergence of superlinear allometric scaling laws is an inherently three-dimensional phenomenon. Moreover, the scaling laws thereby identified allowed us to define a set of metabolic metrics with prognostic value, thus providing added clinical utility to the base findings.

Invasion front dynamics in disordered environments.

Invasion occurs in environments that are normally spatially disordered, however, the effect of such a randomness on the dynamics of the invasion front has remained less understood. Here, we study Fisher's equation in disordered environments both analytically and numerically. Using the Effective Medium Approximation, we show that disorder slows down invasion velocity and for ensemble average of invasion velocity in disordered environment we have [Formula: see text] where [Formula: see text] is the amplitude of disorder and [Formula: see text] is the invasion velocity in the corresponding homogeneous environment given by [Formula: see text]. Additionally, disorder imposes fluctuations on the invasion front. Using a perturbative approach, we show that these fluctuations are Brownian with a diffusion constant of: [Formula: see text]. These findings were approved by numerical analysis. Alongside this continuum model, we use the Stepping Stone Model to check how our findings change when we move from the continuum approach to a discrete approach. Our analysis suggests that individual-based models exhibit inherent fluctuations and the effect of environmental disorder becomes apparent for large disorder intensity and/or high carrying capacities.

Regulation of migration of chemotactic tumor cells by the spatial distribution of collagen fiber orientation.

Collagen fibers, an important component of the extracellular matrix (ECM), can both inhibit and promote cellular migration. In vitro studies have revealed that the fibers' orientations are crucial to cellular invasion, while in vivo investigations have led to the development of tumor-associated collagen signatures (TACS) as an important prognostic factor. Studying biophysical regulation of cell invasion and the effect of the fibers' orientation not only deepens our understanding of the phenomenon, but also helps classify the TACSs precisely, which is currently lacking. We present a stochastic model for random or chemotactic migration of cells in fibrous ECM, and study the role of the various factors in it. The model provides a framework for quantitative classification of the TACSs, and reproduces quantitatively recent experimental data for cell motility. It also indicates that the spatial distribution of the fibers' orientations and extended correlations between them, hitherto ignored, as well as dynamics of cellular motion all contribute to regulation of the cells' invasion length, which represents a measure of metastatic risk. Although the fibers' orientations trivially affect randomly moving cells, their effect on chemotactic cells is completely nontrivial and unexplored, which we study in this paper.

Effect of heterogeneity and spatial correlations on the structure of a tumor invasion front in cellular environments.

Analysis of invasion front has been widely used to decipher biological properties, as well as the growth dynamics of the corresponding populations. Likewise, the invasion front of tumors has been investigated, from which insights into the biological mechanisms of tumor growth have been gained. We develop a model to study how tumors' invasion front depends on the relevant properties of a cellular environment. To do so, we develop a model based on a nonlinear reaction-diffusion equation, the Fisher-Kolmogorov-Petrovsky-Piskunov equation, to model tumor growth. Our study aims to understand how heterogeneity in the cellular environment's stiffness, as well as spatial correlations in its morphology, the existence of both of which has been demonstrated by experiments, affects the properties of tumor invasion front. It is demonstrated that three important factors affect the properties of the front, namely the spatial distribution of the local diffusion coefficients, the spatial correlations between them, and the ratio of the cells' duplication rate and their average diffusion coefficient. Analyzing the scaling properties of tumor invasion front computed by solving the governing equation, we show that, contrary to several previous claims, the invasion front of tumors and cancerous cell colonies cannot be described by the well-known models of kinetic growth, such as the Kardar-Parisi-Zhang equation.

Role of the Interplay Between the Internal and External Conditions in Invasive Behavior of Tumors.

Tumor growth, which plays a central role in cancer evolution, depends on both the internal features of the cells, such as their ability for unlimited duplication, and the external conditions, e.g., supply of nutrients, as well as the dynamic interactions between the two. A stem cell theory of cancer has recently been developed that suggests the existence of a subpopulation of self-renewing tumor cells to be responsible for tumorigenesis, and is able to initiate metastatic spreading. The question of abundance of the cancer stem cells (CSCs) and its relation to tumor malignancy has, however, remained an unsolved problem and has been a subject of recent debates. In this paper we propose a novel model beyond the standard stochastic models of tumor development, in order to explore the effect of the density of the CSCs and oxygen on the tumor's invasive behavior. The model identifies natural selection as the underlying process for complex morphology of tumors, which has been observed experimentally, and indicates that their invasive behavior depends on both the number of the CSCs and the oxygen density in the microenvironment. The interplay between the external and internal conditions may pave the way for a new cancer therapy.

Immunophysical analysis of corneal neovascularization: mechanistic insights and implications for pharmacotherapy.

The cornea lacks adaptive immune cells and vasculature under healthy conditions, but is populated by both cell types under pathologic conditions and after transplantation. Here we propose an immunophysical approach to describe postoperative neovascularization in corneal grafts. We develop a simple dynamic model that captures not only the well-established interactions between innate immunity and vascular dynamics but also incorporates the contributions of adaptive immunity to vascular growth. We study how these interactions determine dynamic changes and steady states of the system as well as the clinical outcome, i.e. graft survival. The model allows us to systematically explore the impact of pharmacological inhibitors of vascular growth on the function and survival of transplanted corneas and search for the optimal time to initiatetherapy. Predictions from our models will help ongoing efforts to design therapeutic approaches to modulate alloimmunity and suppress allograft rejection.

Search efficiency of biased migration towards stationary or moving targets in heterogeneously structured environments.

Efficient search acts as a strong selective force in biological systems ranging from cellular populations to predator-prey systems. The search processes commonly involve finding a stationary or mobile target within a heterogeneously structured environment where obstacles limit migration. An open generic question is whether random or directionally biased motions or a combination of both provide an optimal search efficiency and how that depends on the motility and density of targets and obstacles. To address this question, we develop a simple model that involves a random walker searching for its targets in a heterogeneous medium of bond percolation square lattice and used mean first passage time (〈T〉) as an indication of average search time. Our analysis reveals a dual effect of directional bias on the minimum value of 〈T〉. For a homogeneous medium, directionality always decreases 〈T〉 and a pure directional migration (a ballistic motion) serves as the optimized strategy, while for a heterogeneous environment, we find that the optimized strategy involves a combination of directed and random migrations. The relative contribution of these modes is determined by the density of obstacles and motility of targets. Existence of randomness and motility of targets add to the efficiency of search. Our study reveals generic and simple rules that govern search efficiency. Our findings might find application in a number of areas including immunology, cell biology, ecology, and robotics.