Hirudin suppresses hematogenous metastasis by targeting desmosome junction transition in circulating tumor cell clusters via HIF-1alpha-DSG2 signaling #MMPMID41381723
Zou J; Shi J; Chen Q; Zhu Z; Hu T; Zhang Z; Pan Z; Xu F; Zhu Y; Wu Y; Zhao Y; Wang A; Lu Y; Pan Y; Chen W
Exp Mol Med 2025[Dec]; ? (?): ? PMID41381723show ga
Circulating tumor cell (CTC) clusters, key in metastasis, rely on intercellular junctions for stability. However, the specific mechanisms governing intercellular connections within CTC clusters and the strategy targeting intercellular junctions to break CTC clusters remain elusive. Anticoagulants, commonly used to manage tumor-associated thrombosis, may potentially serve as CTC cluster dissociators, but their effects and mechanisms in inhibiting tumor metastasis are unclear. Hirudin, an anticoagulant peptide was used as a tool drug and found to inhibit breast tumor lung retention and colonization through its disruption of CTC clusters rather than directly inhibiting cell migration. Further research confirmed that within CTC clusters, desmosome junctions play a dominant role in maintaining CTC cluster formation with high expression of related proteins, while adhesion junctions express rarely. Desmoglein 2 (DSG2) mediates conversion between desmosome and adhesion junctions in CTC clusters. When DSG2 is highly expressed, the intercellular junctions within the CTC clusters are mainly composed of desmosomes. Reversely, low expression of DSG2 results in adhesion junctions. In addition, hypoxia-inducible factor-1 alpha (HIF-1alpha) positively controls DSG2-mediated desmosome junctions. Inhibiting HIF-1alpha promotes the conversion from desmosome to adhesion junctions, destabilizing CTC clusters. Hirudin inhibits hematogenous metastasis of breast cancer through suppression of HIF-1alpha-controlled DSG2-mediated desmosome junctions, ultimately leading to the disintegration of CTC clusters. Our findings highlight the therapeutic potential of targeting HIF-1alpha-controlled DSG2-mediated desmosome junction conversion and position hirudin as a promising CTC clusters dissociator optimized for the clinical prevention of breast cancer metastasis.
Exp+Mol+Med 2025 ; ? (?): ?
