多组学整合揭示eccDNAs在弥漫大B细胞淋巴瘤中的致癌作用通过STING信号通路
Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling
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影响因子:6.8
分区:医学2区 Top / 医学：研究与实验2区 肿瘤学2区
发表日期:2024 Aug
作者:
Zijuan Wu, Wei Zhang, Luqiao Wang, Jiayan Leng, Yongle Li, Zhou Fan, Mengtao Zhan, Lei Cao, Yongning Jiang, Yan Jiang, Bing Sun, Jianxin Fu, Jianyong Li, Wenyu Shi, Hui Jin
DOI:
10.1002/ctm2.1815
摘要
染色体外环状DNA（eccDNAs）是一类双链DNA（dsDNA），能够激活DNA感应机制，并与多种疾病的进展及预后相关。尽管eccDNA的作用仍存在争议，但其在弥漫性大B细胞淋巴瘤（DLBCL）中的作用尚未报道。采用环状DNA测序（circle-seq）分析DLBCL中eccDNA的表达谱，并通过原子力显微镜验证eccDNA的存在。利用CCK-8检测和单细胞RNA测序（scRNA-seq）揭示eccDNA激活STING路径，促进细胞增殖。使用化疗药物验证DNA损伤是否诱导eccDNA产生，从而在cGAS非依赖性下激活STING通路。GEO数据库用于验证eccDNA相关基因的预后，动物模型用于研究DNA损伤治疗结合STING抑制剂的抗肿瘤协同作用。结果显示，eccDNAs在DLBCL中广泛表达，并与患者预后相关。eccDNA的升高促进DLBCL的进展。化疗引起的DNA损伤触发eccDNA生成，并在cGAS非依赖性下激活STING信号。此外，STING抑制剂与顺铂联用具有协同抗肿瘤作用。eccDNA由DNA损伤诱导，通过激活STING信号在不依赖cGAS的情况下发挥致癌作用。这为结合化疗与靶向STING的治疗策略提供了理论基础。研究表明，DNA损伤诱导的eccDNA在DLBCL中起到促癌作用，通过激活STING通路，独立于cGAS。这一发现为治疗方案提供新的思路，尤其适用于复发或难治性（R/R）患者，联合化疗与STING抑制剂显著延缓肿瘤进展。
Abstract
Extrachromosomal circular DNAs (eccDNAs), a type of double-stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B-cell lymphoma (DLBCL) has not been reported.Circular DNA sequencing (circle-seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK-8 and scRNA-seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA-related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti-tumour responses.EccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs-induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS-independent manner. Moreover, inhibition of STING exerted a synergistic anti-tumour effect with cisplatin.EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING.EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.