Cisplatin-Induced ecDNA Enhances Tumor Aggressiveness and Accelerates Chemoresistance Acquisition in Gastric Cancer

作者：Huanbo Zhu, Lian Chen, Longtao Huangfu, Gangjian Wang, Huixin Cai, Junbing Chen, Xiaomei Li, Min Liang, Wenmei Li, Yongqi Wang, Shaokun Shu, Shuqin Jia, Jiafu Ji, Xiaofang Xing · 发表于：Journal of Advanced Research · 年份：2026 · DOI：10.1016/j.jare.2026.07.056 · 研究领域：Cancer Cells and Metastasis、Cancer Genomics and Diagnostics、Cancer therapeutics and mechanisms

BACKGROUND: Extrachromosomal DNA (ecDNA), as a dynamic genetic vector, enables tumor cells to exhibit enhanced adaptability under chemotherapeutic stress. However, its functional role in tumor malignancy and the development of drug resistance in gastric cancer (GC) remains unclear. OBJECTIVE: This study aimed to investigate the relationship between chemotherapy and ecDNA in GC, and to explore its potential as a novel therapeutic target. METHODS: We first analyzed our clinical data to reveal associations between ecDNA induction by chemotherapy and metastatic progression. Then we investigated the role of ecDNA in mediating chemoresistance and malignant phenotypes in cisplatin-resistant cell models using WGS, SEM, western blot, qPCR, flow cytometry, and immunofluorescence. RESULTS: We found that neoadjuvant chemotherapy (NAC) promoted ecDNA formation from linear amplicons, which was associated with increased tumor mutational burden, poorer survival, and higher distant metastasis risk. The generation of ecDNA in GC was more likely to originate from chromosomes 5, 7, 8, 9, and 12. In cisplatin-resistant models, ecDNA emergence promoted various malignant phenotypes, including DNA damage repair, G1 arrest, autophagy, proliferation, migration, and invasion, which were attenuated by ecDNA inhibition. EcDNA inhibitors delayed acquired resistance in wild-type cells and showed combinatorial activity with cisplatin in resistant GC, supporting clinical potential. CONCLUSION: Our study reve...