Original Title: Computational ranking identifies Plexin-B2 in circulating tumor cell clustering with monocytes in breast cancer metastasis
Journal: Nature communications
DOI: 10.1038/s41467-025-62862-z
Overview
Circulating tumor cell (CTC) clusters are significantly more effective at seeding metastases than single CTCs, but the molecular mechanisms driving their formation are not fully understood. This study employed a computational ranking system, integrating proteomic data from breast tumors and cell lines with clinical survival data, to identify key proteins involved in this process. The analysis pinpointed Plexin-B2 (PLXNB2) as a top candidate associated with poor patient outcomes. In clinical samples, high PLXNB2 expression was enriched in CTC clusters and correlated with unfavorable overall survival (Hazard Ratio = 2.22). Experiments using mouse models demonstrated that genetic deletion of PLXNB2 in breast cancer cells resulted in a 23-fold reduction in spontaneous lung metastasis. The study further revealed that PLXNB2 on tumor cells interacts with the ligand SEMA4C on other tumor cells to form homotypic (tumor-only) clusters, and with SEMA4A on monocytes to form heterotypic (tumor-immune) clusters, establishing PLXNB2 as a key mediator of metastasis-driving cell aggregation.
Novelty
The novelty of this research lies in its identification of the specific PLXNB2 signaling axis as a central mechanism for both homotypic and heterotypic CTC clustering in breast cancer. The study introduces a computational ranking score that systematically integrates large-scale proteomic datasets with clinical outcome data to successfully prioritize a functionally important therapeutic target from a list of over 600 candidate proteins. While the metastatic potential of CTC clusters was previously established, this work provides a detailed molecular explanation, pinpointing PLXNB2 as the core receptor. A key finding is the dissection of its dual-role in clustering, showing it binds to a specific ligand, SEMA4C, for tumor-to-tumor cell adhesion, and a different ligand, SEMA4A on monocytes, for tumor-to-immune cell adhesion.
Potential Clinical / Research Applications
The findings present several potential clinical and research applications. PLXNB2 and its ligands, SEMA4C and SEMA4A, represent promising therapeutic targets for preventing breast cancer metastasis. The development of monoclonal antibodies or small-molecule inhibitors that block these specific protein interactions could disrupt CTC cluster formation and thereby reduce the risk of metastatic spread. In diagnostics, measuring PLXNB2 levels on CTCs from patient blood samples could serve as a liquid biopsy-based prognostic biomarker to identify individuals at high risk for metastasis who may require more intensive treatment. The in vitro and in vivo models established in this research also provide a robust platform for screening and validating new anti-cluster and anti-metastatic drugs. Future research could extend these findings to investigate the role of the PLXNB2 axis in metastasis to other organs and in other cancer types.
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