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Published on: June 27, 2020
Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING
Zijuan Wu1,2,3, Wei Zhang1,4, Luqiao Wang5
1Lymphoma Center, Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing Medical University, Nanjing, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Highlights:
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.
Insights
Extrachromosomal circular DNAs (eccDNAs) promote diffuse large B-cell lymphoma (DLBCL) by activating the STING pathway. DNA damage induces eccDNAs, offering a therapeutic target for DLBCL treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Extrachromosomal circular DNAs (eccDNAs) are implicated in disease progression but their role in diffuse large B-cell lymphoma (DLBCL) is unreported.
- eccDNAs activate DNA sensing pathways, influencing cellular processes.
Purpose of the Study:
- To investigate the role and significance of eccDNAs in DLBCL pathogenesis.
- To explore the mechanism of eccDNA activation and its impact on DLBCL progression.
- To evaluate therapeutic strategies targeting eccDNA-STING pathway in DLBCL.
Main Methods:
- Circular DNA sequencing (circle-seq) and atomic force microscopy were used to detect eccDNAs in DLBCL.
- CCK-8 and scRNA-seq analyzed eccDNA activation of the STING pathway and cell proliferation.
- Chemotherapeutic drugs and STING inhibitors were used in vitro and in vivo models.
Main Results:
- eccDNAs are widely expressed in DLBCL and correlate with patient prognosis.
- Elevated eccDNA levels promote DLBCL progression.
- DNA damage induces eccDNAs, activating STING signaling independently of cGAS, enhancing proliferation.
- Combined chemotherapy and STING inhibition showed synergistic anti-tumor effects.
Conclusions:
- DNA damage-induced eccDNAs play an oncogenic role in DLBCL by activating STING signaling independently of cGAS.
- Targeting the STING pathway in combination with chemotherapy presents a promising therapeutic strategy for DLBCL, especially for relapsed/refractory cases.
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