The Lost Homeostasis of the Cell: Intrinsic Molecular Dysregulation, Peripheral Microenvironmental Signals, and Higher-Order Systemic Perturbations in the Carcinogenic Cascade — Toward a Unified Multi-Scale Paradigm

Cancer emerges from the progressive breakdown of cellular homeostasis across molecular, microenvironmental, and systemic scales. Despite decades of research, existing frameworks predominantly address these scales in isolation, limiting their ability to represent the emergent phenomena that characterize malignant progression. Here we introduce the Multi-Scale Homeostatic Disruption Theory (MHDT), an integrative modelling framework that couples intrinsic molecular dysregulation, peripheral microenvironmental signals, and higher-order neuro-endocrine-immune perturbations within a single system of coupled nonlinear ordinary differential equations. As an illustrative proof of concept, we generate all reported trajectories, phase portraits, threshold estimates, and sensitivity indices from actual numerical integration of the model equations over a synthetic, biologically plausible parameter regime. A global (Sobol) sensitivity analysis, computed by Saltelli sampling, identifies neural coupling as the leading driver of the simulated homeostatic collapse, with peripheral and systemic couplings next in importance. We provide a specified Bayesian inference interface for future calibration to real data, but we do not claim a posterior fitted to real measurements here; accordingly we compare the model family structurally rather than by fitted information criteria. We give a linear-stability analysis of the homeostatic fixed point—which shows the collapse to be a slow, memory-driven, global nonlinear process rather than a local bifurcation—and a linear-regime thermodynamic argument relating multi-scale coupling to entropy production. Four falsifiable predictions are articulated, including the hypothesis that selective pharmacological blockade of neuro-endocrine loops can partially restore homeostasis in high-dysregulation contexts. All parameter values and derivations are provided for full reproducibility. This work is intended as a conceptual and methodological foundation for a multi-scale view of homeostatic oncology, not as a clinically validated model.