The role of spatial variations of abiotic factors in mediating intratumour phenotypic heterogeneity

We present here a space- and phenotype-structured model of selection dynamics between cancer cells within a solid tumour. In the framework of this model, we combine formal analyses with numerical simulations to investigate in silico the role played by the spatial distribution of abiotic components of the tumour microenvironment in mediating phenotypic selection of cancer cells. Numerical simulations are performed both on the 3D geometry of an in silico multicellular tumour spheroid and on the 3D geometry of an in vivo human hepatic tumour, which was imaged using computerised tomography. The results obtained show that inhomogeneities in the spatial distribution of oxygen, currently observed in solid tumours, can promote the creation of distinct local niches and lead to the selection of different phenotypic variants within the same tumour. This process fosters the emergence of stable phenotypic heterogeneity and supports the presence of hypoxic cells resistant to cytotoxic therapy prior to treatment. Our theoretical results demonstrate the importance of integrating spatial data with ecological principles when evaluating the therapeutic response of solid tumours to cytotoxic therapy

Micro-Capsules in Shear Flow

This paper deals with flow-induced shape transitions of elastic capsules. The state of the art concerning both theory and experiments is briefly reviewed starting with dynamically induced small deformation of initially spherical capsules and the formation of wrinkles on polymerized membranes. Initially non-spherical capsules show tumbling and tank-treading motion in shear flow. Theoretical descriptions of the transition between these two types of motion assuming a fixed shape are at variance with the full capsule dynamics obtained numerically. To resolve the discrepancy, we expand the exact equations of motion for small deformations and find that shape changes play a dominant role. We classify the dynamical phase transitions and obtain numerical and analytical results for the phase boundaries as a function of viscosity contrast, shear and elongational flow rate. We conclude with perspectives on timedependent flow, on shear-induced unbinding from surfaces, on the role of thermal fluctuations, and on applying the concepts of stochastic thermodynamics to these systems.Comment: 34 pages, 15 figure

Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model

Practically, all chemotherapeutic agents lead to drug resistance. Clinically, it is a challenge to determine whether resistance arises prior to, or as a result of, cancer therapy. Further, a number of different intracellular and microenvironmental factors have been correlated with the emergence of drug resistance. With the goal of better understanding drug resistance and its connection with the tumor microenvironment, we have developed a hybrid discrete-continuous mathematical model. In this model, cancer cells described through a particle-spring approach respond to dynamically changing oxygen and DNA damaging drug concentrations described through partial differential equations. We thoroughly explored the behavior of our self-calibrated model under the following common conditions: a fixed layout of the vasculature, an identical initial configuration of cancer cells, the same mechanism of drug action, and one mechanism of cellular response to the drug. We considered one set of simulations in which drug resistance existed prior to the start of treatment, and another set in which drug resistance is acquired in response to treatment. This allows us to compare how both kinds of resistance influence the spatial and temporal dynamics of the developing tumor, and its clonal diversity. We show that both pre-existing and acquired resistance can give rise to three biologically distinct parameter regimes: successful tumor eradication, reduced effectiveness of drug during the course of treatment (resistance), and complete treatment failure

Influence of shear flow on vesicles near a wall: a numerical study

We describe the dynamics of three-dimensional fluid vesicles in steady shear flow in the vicinity of a wall. This is analyzed numerically at low Reynolds numbers using a boundary element method. The area-incompressible vesicle exhibits bending elasticity. Forces due to adhesion or gravity oppose the hydrodynamic lift force driving the vesicle away from a wall. We investigate three cases. First, a neutrally buoyant vesicle is placed in the vicinity of a wall which acts only as a geometrical constraint. We find that the lift velocity is linearly proportional to shear rate and decreases with increasing distance between the vesicle and the wall. Second, with a vesicle filled with a denser fluid, we find a stationary hovering state. We present an estimate of the viscous lift force which seems to agree with recent experiments of Lorz et al. [Europhys. Lett., vol. 51, 468 (2000)]. Third, if the wall exerts an additional adhesive force, we investigate the dynamical unbinding transition which occurs at an adhesion strength linearly proportional to the shear rate.Comment: 17 pages (incl. 10 figures), RevTeX (figures in PostScript

Establishment of a murine epidermal cell line suitable for in vitro and in vivo skin modelling

<p>Abstract</p> <p>Background</p> <p>Skin diseases are a major health problem. Some of the most severe conditions involve genetic disorders, including cancer. Several of these human diseases have been modelled in genetically modified mice, thus becoming a highly valuable preclinical tool for the treatment of these pathologies. However, development of three-dimensional models of skin using keratinocytes from normal and/or genetically modified mice has been hindered by the difficulty to subculture murine epidermal keratinocytes.</p> <p>Methods</p> <p>We have generated a murine epidermal cell line by serially passaging keratinocytes isolated from the back skin of adult mice. We have termed this cell line COCA. Cell culture is done in fully defined media and does not require feeder cells or any other coating methods.</p> <p>Results</p> <p>COCA retained its capacity to differentiate and stratify in response to increased calcium concentration in the cell culture medium for more than 75 passages. These cells, including late passage, can form epidermis-like structures in three-dimensional <it>in vitro </it>models with a well-preserved pattern of proliferation and differentiation. Furthermore, these cells form epidermis in grafting assays <it>in vivo</it>, and do not develop tumorigenic ability.</p> <p>Conclusions</p> <p>We propose that COCA constitutes a good experimental system for <it>in vitro </it>and <it>in vivo </it>skin modelling. Also, cell lines from genetically modified mice of interest in skin biology could be established using the method we have developed. COCA keratinocytes would be a suitable control, within a similar background, when studying the biological implications of these alterations.</p

Interactions between proteins bound to biomembranes

We study a physical model for the interaction between general inclusions bound to fluid membranes that possess finite tension, as well as the usual bending rigidity. We are motivated by an interest in proteins bound to cell membranes that apply forces to these membranes, due to either entropic or direct chemical interactions. We find an exact analytic solution for the repulsive interaction between two similar circularly symmetric inclusions. This repulsion extends over length scales of order tens of nanometers, and contrasts with the membrane-mediated contact attraction for similar inclusions on tensionless membranes. For non circularly symmetric inclusions we study the small, algebraically long-ranged, attractive contribution to the force that arises. We discuss the relevance of our results to biological phenomena, such as the budding of caveolae from cell membranes and the striations that are observed on their coats.Comment: 22 pages, 2 figure

A Functional Role of RB-Dependent Pathway in the Control of Quiescence in Adult Epidermal Stem Cells Revealed by Genomic Profiling

Continuous cell renewal in mouse epidermis is at the expense of a pool of pluripotent cells that lie in a well defined niche in the hair follicle known as the bulge. To identify mechanisms controlling hair follicle stem cell homeostasis, we developed a strategy to isolate adult bulge stem cells in mice and to define their transcriptional profile. We observed that a large number of transcripts are underexpressed in hair follicle stem cells when compared to non-stem cells. Importantly, the majority of these downregulated genes are involved in cell cycle. Using bioinformatics tools, we identified the E2F transcription factor family as a potential element involved in the regulation of these transcripts. To determine their functional role, we used engineered mice lacking Rb gene in epidermis, which showed increased expression of most E2F family members and increased E2F transcriptional activity. Experiments designed to analyze epidermal stem cell functionality (i.e.: hair regrowth and wound healing) imply a role of the Rb-E2F axis in the control of stem cell quiescence in epidermis