Multi-scale modeling reveals angiogenesis-induced drug resistance in brain tumor and predicts a synergistic drug combination targeting EGFR and VEGFR pathways

Abstract

Experimental studies have demonstrated that both the extracellular vasculature, microenvironment and intracellualr molecular network (e.g. epidermal growth factor receptor (EGFR) signaling pathways) are essentially important for brain tumor growth. Some drugs have been developed to inhibit the EGFR signaling pathways. However, how does angiogenesis affect the response of tumor cells to the drug treatment has rarely been mechanistically studied. Therefore, a multiscale model is required to investigate such complex biological systems that contain interactions and feedbacks among multi-levels. In this study, we developed a single cell-based multi-scale spatio-temporal model to simulate more realistic vascular tumor growth and drug response, based on VEGFR signaling pathways, EGFR signaling pathway and cell cycle as well as several microenvironmental factors that determine cell fate switches in a temporal and spatial context. The simulation reconstructed an evolving profile of vascular tumor growth, demonstrating the dynamic interplay between angiogenesis and various types of tumor cells (e.g., migrating, proliferating, apoptosis and quiescent cells). Moreover, we revealed the critical role of angiogenesis in the acquired drug resistance. We further investigated the optimal timing of combing VEGFR inhibition with EGFR inhibition and predicted that the drug combination targeting both EGFR pathway and VEGFR pathway has a synergistic effect. The experimental data validated the prediction of drug synergy, confirming the effectiveness of our model. The developed multiscale model explored mechanistic and functional mechanisms of angiogenesis underlying tumor growth and drug resistance, which advances our understanding of novel mechanisms of drug resistance and provides implications for designing more effective cancer therapies.\n\nAuthor summaryMany targeted therapies have been designed to treat malignant tumors including gliomas, but the clinical effectiveness of these therapies are limited due to the emergence of drug resistance during cancer therapeutics. The mechanisms underlying cancer drug resistance have not been fully understood until now, which restricts the rational designing of robust and effective therapeutics. Increasing number of experimental studies have indicated that angiogenesis plays important role s in influencing the effect of drug treatment. However, how does angiogenesis affect the response of tumor cells to the drug treatment has rarely been mechanistically studied. In this study we developed a single cell-based multi-scale spatio-temporal model to investigate the role of angiogenesis in drug response of brain tumors. The model demonstrated dual roles of angiogenesis in drug treatment of brain tumors and revealed a novel mechanism of angiogenesis-induced drug resistance. Moreover, the model predicted a synergistic drug combination targeting both EGFR and VEGFR pathways with optimal combination timing. This study has been dedicated to elucidate mechanistic and functional mechanisms of angiogenesis underlying tumor growth and drug resistance, providing implications for designing more effective drug combination therapies.