Multiscale model of tumor-derived capillary-like network formation

Solid tumors recruit and form blood vessels, used for maintenance and growth as well as for formation and spread of metastases. Vascularization is therefore a pivotal switch in cancer malignancy: an accurate analysis of its driving processes is a big issue for the development of treatments. In vitro experiments have demonstrated that cultured tumor-derived endothelial cells (TECs) are able to organize in a connected network, which mimics an in vivo capillary-plexus. The process, called tubulogenesis, is promoted by the activity of soluble peptides (such as VEGFs), as well as by the following intracellular calcium signals. We here propose a multilevel approach, reproducing selected features of the experimental system: it incorporates a continuous model of microscopic VEGF-induced events in a discrete mesoscopic Cellular Potts Model (CPM). The two components are interfaced, producing a multiscale framework characterized by a constant flux of information from finer to coarser levels. The simulation results, in agreement with experimental analysis, allow to identify the key mechanisms of network formation. In particular, we provide evidence that the nascent pattern is characterized by precise topological properties, regulated by the initial cell density in conjunction with the degree of the chemotactic response and the directional persistence of cell migration.