Exosomes derived from M2 type tumor-associated macrophages promote osimertinib resistance in non-small cell lung cancer through MSTRG.292666.16-miR-6836-5p-MAPK8IP3 axis

Cancer Cell International

Chunyan Wang¹  Songwen Zhou¹  Hui Sun¹  Qinfang Deng¹  Weiqing Gu¹  Xiaoying Wan²  Boxiong Xie³ 

[1]Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No.507, Zhengmin Road, Yangpu District, 200433, Shanghai, China

[2]Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No.507, Zhengmin Road, Yangpu District, 200433, Shanghai, China

[3]Medical College of Tongji University, 200433, Shanghai, China

[4]Department of Thoracic, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 200433, Shanghai, China

关键词: NSCLC;    M2-type TAM;    Exosomes;    Osimertinib resistance;    MSTRG.292666.16;    miR-6836-5p;    MAPK8IP3;   

DOI  :  10.1186/s12935-022-02509-x

来源: Springer

【 摘 要 】

BackgroundOsimertinib resistance limits the treatment of epidermal growth factor receptor-(EGFR)-mutated non-small-cell lung carcinoma (NSCLC). The mechanisms of osimertinib resistance need to be elucidated to determine alternative treatment strategies. This study explores the role of M2 type tumor-associated macrophage (TAM)-derived exosomal MSTRG.292666.16 in osimertinib resistance, and its related competing endogenous RNA (ceRNA) mechanism.MethodsM2 type TAMs were induced with 200 ng/mL phorbol 12-myristate 13-acetate, 20 ng/mL IL-4 and IL-13, and M2 type macrophage markers were measured by RT-qPCR. Next, the exosomes were isolated and characterized. Tumor formation in nude mice was conducted using H1975 cells under different treatment conditions. Small RNA sequencing was performed on exosomes derived from sensitive and resistant plasma, and ceRNA networks were constructed. Fluorescence in situ hybridization was used to observe the localization of MSTRG.292666.16, and a ceRNA network (MSTRG.292666.16-miR-6836-5p-MAPK8IP3) was selected for further validation.ResultsM2 type TAMs, and M2 type TAM-derived exosomes were successfully induced and isolated. Nude mice results showed that M2 type TAM-derived exosomes and MSTRG.292666.16 overexpression significantly increased tumor volume after administration of osimertinib for 4 weeks. M2 type TAMs were found in the resistant plasma, and MSTRG.292666.16 localized in the cytoplasm of H1975 cells. In addition, the genes in the ceRNA networks were significantly enriched in eight GO terms and seven KEGG pathways, including the MAPK signaling pathway. Subsequently, the levels of MSTRG.292666.16 and MAPK8IP3 significantly increased in both resistant plasma-derived exosomes and M2 type TAM-derived exosomes, while miR-6836-5p levels were significantly reduced. Finally, MSTRG.292666.16, miR-6836-5p, and MAPK8IP3 were part of the same network.ConclusionsM2 type TAM-derived exosomes promoted osimertinib resistance in NSCLC by regulating the MSTRG.292666.16/miR-6386-5p/MAPK8IP3 axis.

【 授权许可】

CC BY