Dissecting cell fate dynamics in pediatric glioblastoma through the lens of complex systems and cellular cybernetics.

Cancers are complex dynamic ecosystems. Reductionist approaches to science are inadequate in characterizing their self-organized patterns and collective emergent behaviors. Since current approaches to single-cell analysis in cancer systems rely primarily on single time-point multiomics, many of the temporal features and causal adaptive behaviors in cancer dynamics are vastly ignored. As such, tools and concepts from the interdisciplinary paradigm of complex systems theory are introduced herein to decode the cellular cybernetics of cancer differentiation dynamics and behavioral patterns. An intuition for the attractors and complex networks underlying cancer processes such as cell fate decision-making, multiscale pattern formation systems, and epigenetic state-transitions is developed. The applications of complex systems physics in paving targeted therapies and causal pattern discovery in precision oncology are discussed. Pediatric high-grade gliomas are discussed as a model-system to demonstrate that cancers are complex adaptive systems, in which the emergence and selection of heterogeneous cellular states and phenotypic plasticity are driven by complex multiscale network dynamics. In specific, pediatric glioblastoma (GBM) is used as a proof-of-concept model to illustrate the applications of the complex systems framework in understanding GBM cell fate decisions and decoding their adaptive cellular dynamics. The scope of these tools in forecasting cancer cell fate dynamics in the emerging field of computational oncology and patient-centered systems medicine is highlighted.