Mathematical modeling reveals a critical role for cyclin D1 dynamics in phenotype switching during glioma differentiation

• An experiment-integrated mathematical model of signaling pathways involved in glioma differentiation was developed.
• Model analysis revealed that bifurcation dynamics of cyclin D1 control the glioma cell phenotype transition from proliferation to differentiation.
• Experimental validation confirmed the critical role of cyclin D1 in glioma phenotype switching.

Glioma differentiation therapy is a novel modality to increase anti-glioma effects using specific drugs to induce glioma cell differentiation to glia-like cells. However, the molecular mechanisms underlying glioma differentiation remain poorly understood. In this study, we built an experiment-integrated mathematical model for glioma differentiation signaling pathways. Our modeling and experimental analysis revealed that a “one-way-switch” bifurcation of cyclin D1 dynamics was critical for controlling the phenotypic transition of glioma cells. We also quantitatively evaluated drug combinations toward a synergistic therapeutic effect. These results provide insights into the molecular mechanisms underlying glioma differentiation and implications for the design of novel therapeutic targets in anti-cancer therapy.