Modeling subtype dynamics and heterogeneity in small cell lung cancer using ordinary differential equations

Small-cell lung cancer (SCLC) exhibits rapid progression and remarkable heterogeneity among four major subtypes (ASCL1, NEUROD1, POU2F3, YAP1). These subtypes interconvert through poorly understood regulatory mechanisms. We developed an ordinary differential equation (ODE) framework centered on key transcription factors to model the dynamical formation of SCLC subtypes. Automated exploration of the parameter space revealed multiple stable attractors corresponding to experimentally observed subtypes and predicted coexistence of mixed states under identical conditions. The model reproduced stepwise subtype transitions and identified a stable intermediate ASCL1 expression level consistent with single-cell transcriptomics. This systems-level approach provides a quantitative landscape for SCLC subtype dynamics, illuminating how regulatory feedbacks and parameter perturbations drive phenotypic plasticity and tumor heterogeneity.