Fusobacterium nucleatum promotes colorectal cancer cells adhesion to endothelial cells and facilitates extravasation and metastasis by inducing ALPK1/NF-κB/ICAM1 axis

Ying Zhang; Lu Zhang; Sheng Zheng; Mengjie Li; Chaochao Xu; Dingjiacheng Jia; Yadong Qi; Tongyao Hou; Lan Wang; Boya Wang; Aiqing Li; Shujie Chen; Jianmin Si; Wei Zhuo

doi:10.1080/19490976.2022.2038852

Fusobacterium nucleatum promotes colorectal cancer cells adhesion to endothelial cells and facilitates extravasation and metastasis by inducing ALPK1/NF-κB/ICAM1 axis

Gut Microbes. 2022 Jan-Dec;14(1):2038852. doi: 10.1080/19490976.2022.2038852.

Authors

Ying Zhang^{1

2

3}, Lu Zhang^{4

2

3}, Sheng Zheng^{2

3

5}, Mengjie Li^{1

2

3}, Chaochao Xu^{1

2

3}, Dingjiacheng Jia^{2

3

5}, Yadong Qi^{1

2

3}, Tongyao Hou^{1

2

3}, Lan Wang^{1

2

3}, Boya Wang^{3

6}, Aiqing Li^{1

2

3}, Shujie Chen^{1

2

3}, Jianmin Si^{1

2

3}, Wei Zhuo^{4

2

3}

Affiliations

¹ Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Cancer Center, Zhejiang University, Hangzhou, China.
³ Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
⁴ Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁵ Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
⁶ Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and Fusobacterium nucleatum (F. nucleatum) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of F. nucleatum in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that F. nucleatum enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that F. nucleatum induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of F. nucleatum in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.

Keywords: ALPK1; Gut microbes; ICAM1; adhesion; colorectal cancer metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / microbiology
Endothelial Cells / metabolism
Fusobacterium nucleatum / metabolism
Gastrointestinal Microbiome*
Humans
Intercellular Adhesion Molecule-1 / genetics
NF-kappa B / genetics
NF-kappa B / metabolism
Protein Kinases / metabolism

Substances

ICAM1 protein, human
NF-kappa B
Intercellular Adhesion Molecule-1
Protein Kinases
ALPK1 protein, human

Grants and funding

This work was supported by the National Natural Science Foundation of China [81972276, 82173040, 31771540]; Zhejiang Province Public Welfare Technology Research Project [LGD20H030002, LGD21H160002]; Zhejiang Provincial Medical and Health Science and Technology Project [2019KY412, 2019RC043, 2021RC070, 2022KY825]; Natural Science Foundation of Zhejiang Province [LYY19H310011, Q22H169506] and Fundamental Research Funds for the Central Universities (2021QNA7004).