Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast...

Area of Science:

• Oncology
• Cell Biology
• Cancer Metastasis Research

Background:

• Circulating tumor cells (CTCs) are crucial for cancer metastasis, but their aggregation mechanisms are not fully understood.
• CTC clusters, particularly in triple-negative breast cancer, show higher metastatic potential than single CTCs.
• Understanding CTC aggregation is key to developing effective anti-metastasis therapies.

Purpose of the Study:

• To elucidate the cellular and molecular mechanisms behind circulating tumor cell cluster formation.
• To investigate the role of CD44 in CTC aggregation and subsequent metastasis.
• To identify potential therapeutic targets for blocking polyclonal metastasis mediated by CTC clusters.

Main Methods:

• Intravital multiphoton microscopic imaging of patient-derived xenograft models.
• Analysis of CD44 expression in circulating tumor cells and clusters.
• Functional assays to assess the impact of CD44 depletion on tumor cell aggregation and metastasis.
• Investigation of molecular interactions involving CD44, PAK2, and FAK signaling.

Main Results:

• Circulating tumor cell clusters form through aggregation of individual cells, not collective migration.
• CD44-positive CTC clusters exhibit enhanced tumorigenesis and promote polyclonal metastasis.
• CD44 homophilic interactions are essential for multicellular aggregation and CD44-PAK2 signaling activation.
• Depletion of CD44 inhibited tumor cell aggregation and reduced PAK2 levels.

Conclusions:

• CD44-mediated homophilic interactions drive circulating tumor cell cluster formation and polyclonal metastasis.
• CD44+ CTC clusters are significant indicators of poor prognosis in breast cancer patients.
• Targeting CD44 interactions presents a promising therapeutic strategy to inhibit metastasis and improve clinical outcomes.