Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis

Yibing Han, Takeshi Tomita, Masayoshi Kato, Norihiro Ashihara, Yumiko Higuchi, Hisanori Matoba, Weiyi Wang, Hikaru Hayashi, Yuji Itoh, Satoshi Takahashi, Hiroshi Kurita, Jun Nakayama, Nobuo Okumura and Sachie Hiratsuka ()
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Yibing Han: Shinshu University School of Medicine
Takeshi Tomita: Shinshu University School of Medicine
Masayoshi Kato: Shinshu University School of Medicine
Norihiro Ashihara: Shinshu University School of Medicine
Yumiko Higuchi: Shinshu University
Hisanori Matoba: Shinshu University School of Medicine
Weiyi Wang: Shinshu University School of Medicine
Hikaru Hayashi: Shinshu University School of Medicine
Yuji Itoh: Tohoku University
Satoshi Takahashi: Tohoku University
Hiroshi Kurita: Shinshu University School of Medicine
Jun Nakayama: Shinshu University School of Medicine
Nobuo Okumura: Shinshu University
Sachie Hiratsuka: Shinshu University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Primary tumor cells metastasize to a distant preferred organ. However, the most decisive host factors that determine the precise locations of metastases in cancer patients remain unknown. We have demonstrated that post-translational citrullination of fibrinogen creates a metastatic niche in the vulnerable spots. Pulmonary endothelial cells mediate the citrullination of fibrinogen, changing its conformation, surface charge, and binding properties with serum amyloid A proteins (SAAs), to make it a host tissue-derived metastatic pathogen. The human-specific SAAs-citrullinated fibrinogen (CitFbg) complex recruits cancer cells to form a protein-metastatic cell aggregation in humanized SAA cluster mice. Furthermore, a CitFbg peptide works as a competitive inhibitor to block the homing of metastatic cells into the SAAs-CitFbg sites. The potential metastatic sites in the lungs of patients are clearly visualized by our specific antibody for CitFbg. Thus, CitFbg deposition displays metastatic risks for cancer patients, and the citrullinated peptide is a new type of metastasis inhibitor.

Date: 2023
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DOI: 10.1038/s41467-023-40371-1

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