Single‐cell RNA‐seq dissecting heterogeneity of tumor cells and comprehensive dynamics in tumor microenvironment during lymph nodes metastasis in gastric cancer

转移 癌细胞 淋巴 癌症研究 肿瘤微环境 癌症 细胞 生物 肿瘤异质性 核糖核酸 肿瘤细胞 医学 病理 基因 遗传学
作者
Yan Qian,Ertao Zhai,Sile Chen,Yinan Liu,Yan Ma,Junting Chen,Jianqiu Liu,Changjiang Qin,Qin Cao,Jianhui Chen,Shirong Cai
出处
期刊:International Journal of Cancer [Wiley]
卷期号:151 (8): 1367-1381 被引量:36
标识
DOI:10.1002/ijc.34172
摘要

Lymph node metastasis is the common metastasis route of gastric cancer. However, until now, heterogeneities of tumor cells and tumor microenvironment in primary tumors (PT) and metastatic lymph nodes (MLN) of gastric cancer (GC) remains uncharacterized. In our study, single cell RNA sequencing was performed on tissues from PT and MLN of gastric cancer. Trajectory analysis and function enrichment analyses were conducted to decode the underlying mechanisms contributing to LN metastasis of gastric cancer. Heterogeneous composition of immune cells and distinct intercellular interactions in PT and MLN were analyzed. Based on the generated single cell transcriptome profiles, dynamics of gene expressions in cancer cells between PT and MLN were characterized. Moreover, we reconstructed the developmental trajectory of GC cells' metastasis to LN and identified two subtypes of GC cells with distinct potentials of having malignant biological behaviors. We characterized the repression of neutrophil polarization associated genes, like LCN2, which would contribute to LN metastasis, and histochemistry experiments validated our findings. Additionally, heterogeneity in neutrophils, rather than macrophages, was characterized. Immune checkpoint associated interaction of SPP1 was found active in MLN. In conclusion, we decode the dynamics of tumor cells during LN metastasis in GC and to identify a subtype of GC cells with potentials of LN metastasis. Our data indicated that the disordering the neutrophils polarization and maturation and the activation of immune checkpoint SPP1 might contribute to LN metastasis in GC, providing a novel insight on the mechanism and potential therapeutic targets of LN metastasis in GC.
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