Randelovic, T. | bioRxiv Science

bioRxiv2023

Modelling glioblastoma resistance to temozolomide. Combination of spheroid and mathematical models to simulate cellular adaptation in vitro.

AO_SCPLOWBSTRACTC_SCPLOWDrug resistance is one of the biggest challenges in the fight against cancer. In particular, in the case of glioblastoma, the most lethal brain tumour, resistance to temozolomide (the standard of care drug for chemotherapy in this tumour), is one of the main reasons behind treatment failure and hence responsible for the poor prognosis of patients diagnosed with this disease. In this paper, we combine the power of three-dimensional in vitro experiments of treated glioblastoma spheroids with mathematical models of tumour evolution and adaptation. We use a novel approach based on internal variables for modelling the acquisition of resistance to temozolomide that is observed in a group of treated spheroids in the experiments. These internal variables describe the cells phenotypic state, which depends on the history of drug exposure and affects cell behaviour. We use model selection to determine the most parsimonious model and calibrate it to reproduce the experimental data, obtaining a high level of agreement between the in vitro and in silico outcomes. A sensitivity analysis is carried out to investigate the impact of each model parameter in the predictions. More importantly, we show the utility of our model for answering biological questions, such as what is the intrinsic adaptation mechanism, or for separating the sensitive and resistant populations. We conclude that the proposed in silico framework, in combination with experiments, can be useful to improve our understanding of the mechanisms behind drug resistance in glioblastoma and to eventually set some guidelines for the design of new treatment schemes.

cancer biology↗

bioRxiv2021

A mechanobiological model for tumor spheroids evolution: application to glioblastoma

Spheroids are in vitro spherical structures of cell aggregates, eventually cultured within a hydrogel matrix, that are used, among other applications, as a technological platform to investigate tumor formation and evolution. Several interesting features can be replicated using this methodology, such as cell communication mechanisms, the effect of gradients of nutrients, or the creation of realistic 3D biological structures. In this paper, we propose a continuum mechanobiological model which accounts for the most relevant phenomena that take place in tumor spheroids evolution under in vitro suspension, namely, nutrients diffusion in the spheroid, kinetics of cellular growth and death, and mechanical interactions among the cells. The model is qualitatively validated, after calibration of the model parameters, versus in vitro experiments of spheroids of different glioblastoma cell lines. This preliminary validation allowed us to conclude that glioblastoma tumor spheroids evolution is mainly driven by mechanical interactions of the cell aggregate and the dynamical evolution of the cell population. In particular, it is concluded that our model is able to explain quite different setups, such as spheroids growth (up to six times the initial configuration for U-87 MG cell line) or shrinking (almost half of the initial configuration for U-251 MG cell line); as the result of the mechanical interplay of cells driven by cellular evolution. Indeed, the main contribution of this work is to link the spheroid evolution with the mechanical activity of cells, coupled with nutrient consumption and the subsequent cell dynamics. All this information can be used to further investigate mechanistic effects in the evolution of tumors and their role in cancer disease. Author summarySpheroids structures of cell aggregates are an available experimental platform to analyze the evolution and drug response of solid tumors. In particular, the dynamics of different glioblastoma cell lines have been studied in this work using spheroids. Interestingly, very different behaviors were observed, from a half of the initial configuration shrinking for U-251 MG cell line to six times the initial configuration growth for U-87 MG cell line. These results were replicated by means of a coupled mathematical model which accounts for nutrients diffusion in the spheroid, kinetics of cellular growth and death, and mechanical interactions among the cells. Tumor growth or shrinkage can be explained from a continuum mechanics view driven by cell activity and nutrients availability. This modeling put the focus on mechanistic effects and is aligned with novel experimental techniques to quantify the mechanical microenvironment in tumors. These techniques may be combined with the approach presented in this work to further investigate the role of mechanics in cancer disease.

biophysics↗