Developmental Organization and Adaptive Signaling Dependencies in Multicellular Tumor Ecosystems: A Testable Hypothesis

Developmental reprogramming, stromal protection and compensatory signaling each contribute to cancer adaptation, yet they do not establish that the developmental configuration of a multicellular tumor determines the functional route recruited after perturbation. We propose Developmental Multicellular Ecosystem Plasticity (DMEP) as a falsifiable framework connecting these otherwise distinct observations. DMEP-1 concerns reproducible developmental organization of tumor-associated compartments. DMEP-2A proposes causal conditioning of post-perturbation intercellular dependency identity; DMEP-2B proposes a prospective observational association without claiming causality. DMEP-3 requires added held-out predictive value beyond genotype, cell composition, baseline expression, functional signaling and injury or microenvironment-memory features. We critically distinguish developmental states, spatial proximity, inferred ligand–receptor communication, demonstrated functional dependency, acquired compensation and treatment prediction. Evidence from colorectal, liver, lung, pancreatic and breast cancer offers complementary precedents, not a completed validation chain. We specify rival models and adequate negative tests requiring verified perturbation, independent functional endpoints, biological replication and sufficient precision to exclude meaningful effects. DMEP thereby identifies a narrow experimental and computational challenge rather than presenting a confirmed universal mechanism or clinical biomarker.