# Hirudin suppresses hematogenous metastasis by targeting desmosome junction transition in circulating tumor cell clusters via HIF-1α–DSG2 signaling

## TL;DR

Hirudin, an anticoagulant, can break up cancer cell clusters that help spread breast cancer, potentially reducing metastasis.

## Contribution

Hirudin is shown to disrupt CTC clusters by targeting HIF-1α–DSG2 signaling, offering a new strategy to prevent breast cancer metastasis.

## Key findings

- Hirudin inhibits breast cancer metastasis by breaking up CTC clusters.
- Desmosome junctions, mediated by DSG2, are crucial for CTC cluster stability.
- HIF-1α controls DSG2 expression, and its inhibition destabilizes CTC clusters.

## Abstract

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-1α) positively controls DSG2-mediated desmosome junctions. Inhibiting HIF-1α promotes the conversion from desmosome to adhesion junctions, destabilizing CTC clusters. Hirudin inhibits hematogenous metastasis of breast cancer through suppression of HIF-1α-controlled DSG2-mediated desmosome junctions, ultimately leading to the disintegration of CTC clusters. Our findings highlight the therapeutic potential of targeting HIF-1α-controlled DSG2-mediated desmosome junction conversion and position hirudin as a promising CTC clusters dissociator optimized for the clinical prevention of breast cancer metastasis.

Breast cancer is a leading cause of death among women, often due to the spread of cancer cells to other parts of the body. This study explores how hirudin, which prevents blood clots, might help stop this spread. The researchers focused on circulating tumor cell (CTC) clusters, which can lead to new tumors. The study involved experiments with breast cancer cells and mice to see how hirudin affects CTC clusters. The researchers found that hirudin can break up these clusters by interfering with proteins that help the cells stick together. This is important because breaking up the clusters could reduce the chance of cancer spreading. The results show that hirudin not only reduced the size and number of CTC clusters but also made it harder for them to form new tumors in the lungs.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.