Cell fate dynamics reconstruction identifies TPT1 and PTPRZ1 feedback loops as master regulators of differentiation in pediatric glioblastoma-immune cell networks

Abstract

ABSTRACTPediatric glioblastoma is a complex dynamical disease that is difficult to treat due to its multiple adaptive behaviors driven largely by phenotypic plasticity. Integrated data science and network theory pipelines offer novel approaches to study glioblastoma cell fate dynamics, particularly phenotypic transitions over time. Here we used various single-cell trajectory inference algorithms to infer signaling dynamics regulating pediatric glioblastoma-immune cell networks. We identified GATA2, PTPRZ1, TPT1, MTRNR2L1/2, OLIG1/2, SOX11, PDGFRA, EGFR, S100B, WNT, TNFα, and NF-kB as critical transition genes or signals regulating glioblastoma-immune network dynamics, revealing potential clinically relevant targets. Further, we reconstructed glioblastoma cell fate attractors and found complex bifurcation dynamics within glioblastoma phenotypic transitions, suggesting that a causal pattern may be driving glioblastoma evolution and cell fate decision-making. Together, our findings have implications for the development of targeted therapies against glioblastoma, and the continued integration of quantitative approaches to understand pediatric glioblastoma tumour-immune interactions.