Autophagic flux modulates tumor heterogeneity and lineage plasticity in SCLC.

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 ( ; ; GFP-LC3-RFP-LC3△G), we tracked autophagic flux to investigate its effects on SCLC biology. Additional 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. , 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 and underscores its critical role in driving SCLC heterogeneity and plasticity, offering potential therapeutic insights.