Mathematical modeling of the proliferation gradient in multicellular tumor spheroids

MultiCellular Tumor Spheroids are 3D cell cultures that can accurately reproduce the behavior of solid tumors. It has been experimentally observed that large spheroids exhibit a decreasing gradient of proliferation from the periphery to the center of these multicellular 3D models: the proportion of proliferating cells is higher in the periphery while the non-proliferating quiescent cells increase in depth. In this paper, we propose to investigate the key mechanisms involved in the establishment of this gradient with a Partial Differential Equations model that mimics the experimental set-up of growing spheroids under different nutrients supply conditions. The model consists of mass balance equations on the two cell populations observed in the data: the proliferating cells and the quiescent cells. The spherical symmetry is used to rewrite the model in radial and relative coordinates. Thanks to a rigorous data postprocessing the model is then fit and compared quantitatively with the experimental quantification of the percentage of proliferating cells from EdU immunodetection on 2D spheroid cryosection images. The results of this calibration show that the proliferation gradient observed in spheroids can be quantitatively reproduced by our model. (C) 2018 Elsevier Ltd. All rights reserved.