Genomic Maxwell's Demon Control of Cancer Cell Fates: Integrated Biophysical Mechanisms of Fate Commitment

Molecular biology has revealed immense spatiotemporal complexity in cancer regulatory networks. A fundamental physical question remains: Does a physical principle exist that governs how this complexity self-organizes into genome-wide fate commitment and determines whether and when that commitment becomes irreversible? We address this question at the coarse-grained level of genome-wide expression dynamics through integrated biophysical analyses of time-series transcriptomes from two cancer systems under four conditions: MCF-7 human breast cancer cells stimulated with heregulin (HRG) or epidermal growth factor (EGF), and HL-60 human leukemia cells stimulated with all-trans retinoic acid (atRA) or dimethyl sulfoxide (DMSO). This study further develops our previous framework in which the critical point (CP) gene ensemble regulates self-organized criticality (SOC) in the whole expression system (WES), with CP-state changes triggering genome-wide expression avalanches during cell-fate transitions. Here, SOC control unifies information thermodynamics with genome-engine dynamics in an open, non-equilibrium WES, maintaining a critical dynamic balance between homeostatic stability and fate-guiding critical transitions. The CP performs two integrated roles. As a genomic Maxwell's demon (MD) operator, the CP links information acquisition to feedback-associated state rewriting; reconfiguration of the CP's bimodal expression pattern provides operational rewritable memory. As an SOC controller, it synchronizes with the genome attractor and generates the dominant contribution to work in expression space, driving genome-wide reorganization. Thermodynamic phase synchronization between the CP and the peripheral expression system (PES; the WES excluding the CP), together with information-work coupling, integrates these information-thermodynamic and dynamical roles. Across all four conditions, the CP guides both thermodynamic and dynamical phase synchronization to regulate fate commitment and subsequent genome-wide execution. The timing of information-work coupling distinguishes differentiation-inducing HRG, atRA, and DMSO from proliferative EGF. Based on these results, we propose four criteria for the irreversible arrow of cell-fate change in expression space and define time-gated rules for dynamic cancer-fate control. These criteria provide a testable framework for assessing physical thermodynamic irreversibility through entropy calibration and measurement of outward entropy export.