Multiple types of data are required to identify the mechanisms influencing the spatial expansion of melanoma cell colonies

Abstract

BackgroundThe expansion of cell colonies is driven by a delicate balance of several mechanisms including cell motility, cell–to–cell adhesion and cell proliferation. New approaches that can be used to independently identify and quantify the role of each mechanism will help us understand how each mechanism contributes to the expansion process. Standard mathematical modelling approaches to describe such cell colony expansion typically neglect cell–to–cell adhesion, despite the fact that cell–to-cell adhesion is thought to play an important role.ResultsWe use a combined experimental and mathematical modelling approach to determine the cell diffusivity, D, cell–to–cell adhesion strength, q, and cell proliferation rate, λ, in an expanding colony of MM127 melanoma cells. Using a circular barrier assay, we extract several types of experimental data and use a mathematical model to independently estimate D, q and λ. In our first set of experiments, we suppress cell proliferation and analyse three different types of data to estimate D and q. We find that standard types of data, such as the area enclosed by the leading edge of the expanding colony and more detailed cell density profiles throughout the expanding colony, does not provide sufficient information to uniquely identify D and q. We find that additional data relating to the degree of cell–to–cell clustering is required to provide independent estimates of q, and in turn D. In our second set of experiments, where proliferation is not suppressed, we use data describing temporal changes in cell density to determine the cell proliferation rate. In summary, we find that our experiments are best described using the range D=161−243μm2hour−1, q=0.3−0.5 (low to moderate strength) and λ=0.0305−0.0398hour−1, and with these parameters we can accurately predict the temporal variations in the spatial extent and cell density profile throughout the expanding melanoma cell colony.ConclusionsOur systematic approach to identify the cell diffusivity, cell–to–cell adhesion strength and cell proliferation rate highlights the importance of integrating multiple types of data to accurately quantify the factors influencing the spatial expansion of melanoma cell colonies.

Spatio-temporal morphology changes in and quenching effects on the 2D spreading dynamics of cell colonies in both plain and methylcellulose-containing culture media

“…In this case, carcinoma cells are softer than normal cells [32] and the mismatch in cell elasticity causes several speed "bursts" in which the cancer cell relaxes from a largely deformed shape and consequently, its translational motion increases. The above-mentioned shows that experimental colony dynamic data, from single cells to cell clusters, are of interest for interpreting the influence of spatio-temporal heterogeneities on the colony spreading mechanism [14], in which structural and dynamic characteristics of the medium interfere with molecular recognition-dependent functionalities [33].…”

Standard melanoma-associated markers do not identify the MM127 metastatic melanoma cell line

“…For example, MM127 cells have been used in ultraviolet radiation studies 10 , gene-based studies 11 , drug-response studies 12 and in other melanoma-associated research. Some of our previous work involves investigating how the balance of the rate of cell migration and the rate of cell proliferation affects the collective spreading of a population of MM127 melanoma cells 13 . In this previous study we describe results from an in vitro monoculture circular barrier assay 14,15 , and we use a discrete random walk mathematical model to quantify the rates of cell migration and cell proliferation in the experiment.…”

Investigating the Reproducibility of In Vitro Cell Biology Assays Using Mathematical Models

“…in in vitro cell biology assays and predicting experimental observations for over two decades [14,76,77,100,104,109,115]. In general, there are two forms of mathematical models to describe the collective cell spreading.…”

“…However, discrete models are more computationally expensive, due to the number of realisations required to obtain statistically averaged results [52,109,111,115].…”

“…Treloar et al extract multiple types of data from circular barrier assays and apply both discrete and continuum models to quantify cell diffusivity, cell proliferation, and cellto-cell adhesion of melanoma cells [115]. They also find that with different initial cell numbers, the estimated parameter values are not the same [115].…”