Single‐cell RNA‐seq dissecting heterogeneity of tumor cells and comprehensive dynamics in tumor microenvironment during lymph nodes metastasis in gastric cancer. Issue 8 (4th July 2022)

• Record Type: Journal Article
• Authors: Qian, Yan; Zhai, Ertao; Chen, Sile; Liu, Yinan; Ma, Yan; Chen, Junting; Liu, Jianqiu; Qin, Changjiang; Cao, Qin; Chen, Jianhui; Cai, Shirong
• Is Part Of: International journal of cancer. Volume 151:Issue 8(2022)
• Page Start: 1367
• Page End: 1381
• Publication Date: 2022-07-04
• Subjects: gastric cancer -- heterogeneity -- lymph node metastasis -- single‐cell RNA sequencing -- tumor microenvironment; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34172
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: 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. What's new?: The lymph nodes are the most common sites of metastasis in the progression of gastric cancer. Although it remains unclear, the impetus of gastric tumor cells to metastasize presumably is linked to the acquisition of molecular changes that enable metastatic abilities. In our study, the authors applied single cell RNA sequencing to identify mechanisms underlying lymph node metastasis in gastric cancer. Analyses identified distinct subtypes of gastric cancer cells, one of which had a high potential for lymph node metastasis. Metastatic ability was associated with disordered neutrophil polarization and maturation and activation of the immune regulator SPP1.