Cisplatin (DDP) resistance remains a major therapeutic obstacle in non-small-cell lung cancer (NSCLC).Tumor-associated macrophages (TAMs) are known to promote chemoresistance via exosomal signals, but whether exosomal long non-coding RNA NEAT1 contributes to this process is unclear.In this study, we found that exosomes derived from DDP-treated macrophages were enriched with NEAT1 and delivered it to A549 cells.This transfer enhanced the DNA damage response, promoted cell-cycle progression, and reduced DDP-induced apoptosis.Through RNA-sequencing and luciferase reporter assays, we identified MAD1L1 as a key downstream target of NEAT1.NEAT1 was enriched at the MAD1L1 promoter, upregulated its expression, and subsequently suppressed the p53/p21/Bax axis, thereby fostering a chemoresistant phenotype.In vivo, exosomal NEAT1 promoted tumor growth in DDP-treated xenografts, while NEAT1 knockdown reversed this effect and restored p53 pathway activity.Collectively, our work unveils a novel TAM-exosome-NEAT1-MAD1L1/p53 signaling axis that drives cisplatin resistance in lung adenocarcinoma, highlighting NEAT1 and its intercellular delivery as potential therapeutic targets to overcome chemoresistance.
Yang et al. (Wed,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: