Front Oncol. 2024 ;14 1509183
Introduction: Small cell lung cancer (SCLC) is characterized by significant heterogeneity and plasticity, contributing to its aggressive progression and therapy resistance. Autophagy, a conserved cellular process, is implicated in many cancers, but its role in SCLC remains unclear.
Methods: Using a genetically engineered mouse model (Rb1fl/fl ; Trp53fl/fl ; GFP-LC3-RFP-LC3△G), we tracked autophagic flux in vivo to investigate its effects on SCLC biology. Additional in vitro experiments were conducted to modulate autophagic flux in NE and non-NE SCLC cell lines.
Results: Tumor subpopulations with high autophagic flux displayed increased proliferation, enhanced metastatic potential, and neuroendocrine (NE) characteristics. Conversely, low-autophagic flux subpopulations exhibited immune-related signals and non-NE traits. In vitro, increasing autophagy induced NE features in non-NE cell lines, while autophagy inhibition in NE cell lines promoted non-NE characteristics.
Discussion: This study provides a novel model for investigating autophagy in vivo and underscores its critical role in driving SCLC heterogeneity and plasticity, offering potential therapeutic insights.
Keywords: SCLC; autophagic flux; genetically engineered mouse model; heterogeneity; lineage transition; plasticity; small cell lung cancer