期刊
ONCOGENE
卷 40, 期 12, 页码 2296-2308出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-01722-8
关键词
-
资金
- National Natural Science Foundation of China [81772641, 81902510, 81302119, 81972313, 81972822]
The study found that LNM-GCs specifically educated BM-MSCs via secretory exosomes, with exosomal Wnt5a identified as a key protein. Exosomes enriched with Wnt5a induced YAP dephosphorylation in BM-MSCs, while those lacking Wnt5a had the opposite effect. Inhibition of the YAP signaling pathway blocked the reprogramming of BM-MSCs by LNM-GC exosomes and serum exosomes.
Lymph node metastasis (LNM), a common metastatic gastric-cancer (GC) route, is closely related to poor prognosis in GC patients. Bone marrow-derived mesenchymal stem cells (BM-MSCs) preferentially engraft at metastatic lesions. Whether BM-MSCs are specifically reprogrammed by LNM-derived GC cells (LNM-GCs) and incorporated into metastatic LN microenvironment to prompt GC malignant progression remains unknown. Herein, we found that LNM-GCs specifically educated BM-MSCs via secretory exosomes. Exosomal Wnt5a was identified as key protein mediating LNM-GCs education of BM-MSCs, which was verified by analysis of serum exosomes collected from GC patients with LNM. Wnt5a-enriched exosomes induced YAP dephosphorylation in BM-MSCs, whereas Wnt5a-deficient exosomes exerted the opposite effect. Inhibition of YAP signaling by verteporfin blocked LNM-GC exosome- and serum exosome-mediated reprogramming in BM-MSCs. Analysis of MSC-like cells obtained from metastatic LN tissues of GC patients (GLN-MSCs) confirmed that BM-MSCs incorporated into metastatic LN microenvironment, and that YAP activation participated in maintaining their tumor-promoting phenotype and function. Collectively, our results show that LNM-GCs specifically educated BM-MSCs via exosomal Wnt5a-elicited activation of YAP signaling. This study provides new insights into the mechanisms of LNM in GC and BM-MSC reprogramming, and will provide potential therapeutic targets and detection indicators for GC patients with LNM.
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