Differential gene expression in paired H1092_Baf vs. H1092

Small cell lung cancer (SCLC) is characterized by significant heterogeneity and plasticity, which contribute to its aggressive progression and resistance to therapy. Understanding the underlying mechanisms of these features is essential for improving treatment outcomes. Autophagy, a conserved cellular process, plays a role in many cancers; however, its specific function in SCLC remains unclear. Utilizing a genetically engineered mouse model (Rb1fl/fl; Trp53fl/fl; GFP-LC3-RFP-LC3△G), we tracked autophagic flux in vivo to assess its effects on SCLC biology. Tumor subpopulations with high autophagic flux exhibited increased proliferation, enhanced metastatic potential, and neuroendocrine (NE) characteristics, whereas those with low autophagic flux displayed more immune-related signals and non-NE traits. In vitro modulation of autophagic flux further corroborated these findings: the autophagy activator trehalose induced NE features in non-NE cell lines (DMS114), while the autophagy inhibitor Bafilomycin A1 promoted non-NE characteristics in NE cell lines (H1092). This study provides a model for investigating autophagy in vivo and underscores its role in the heterogeneity and plasticity of SCLC.