Lymph node metastasis-derived gastric cancer cells educate bone marrow-derived mesenchymal stem cells via YAP signaling activation by exosomal Wnt5a

Mei Wang,Feng Huang,Bo Shen,Xinxin Zhao,Haibo Dong,Jiaying Huang,Wei Zhu,Xin Sha,Wenrong Xu,Wanjun Yu,Lin Wang,Rong Qiu,Zheng Gong

doi:10.1038/s41388-021-01722-8

Abstract

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.

Highlights

Paracrine effects of lymph node metastasis (LNM)-GC-mediated education of Bone marrow-derived mesenchymal stem cells (BM-MSCs) are regulated by secretory exosomes
Metastases occurred only in the group of BM-MSCs treated with SGC-7901 exosomes (Supplementary Fig. 2). These results suggest that LNM-derived GC cells (LNM-GCs) exosomes showed an enhanced capability to educate BM-MSCs, further validating the notion that exosomes play a critical role in this process and indicating that LNM-GC-educated BM-MSCs enable primary GCs to acquire the ability to metastasize to lymph nodes (LNs)
Our present study shows that LNM-GCs reprogrammed BM-MSCs to promote GC migration and invasion and that they promoted lymphangiogenesis via activation of Yes-associated protein (YAP) signaling by exosomal Wnt5a

Summary

Introduction

Lymph node metastasis-derived gastric cancer cells educate bone marrow-derived mesenchymal stem cells. Metastasis-associated MSCs are found in the metastatic LN and liver tissues of breast-cancer patients [12]. These findings suggest that BMMSCs preferentially engraft at metastatic sites, and are educated by metastatic cancer cells to incorporate into the metastatic microenvironment. Whether BM-MSCs are educated and directly incorporated into the LN microenvironment to promote the malignant progression of GC after LNM remains unknown. We first compared metastatic LN-derived GC cells (LNM-GCs) and primary GC-derived cancer cells (primary GCs) in their ability to educate BM-MSCs. we investigated the critical paracrine and molecular factors participating in LNM-GC-mediated education of BMMSCs. we examined the downstream signaling involved in this process. MSC-like cells derived from regional LNM and serum samples of GC patients with and without regional LNM were included in our analysis

Results

Discussion

Compliance with ethical standards