Computational ranking identifies Plexin-B2 in circulating tumor cell clustering with monocytes in breast cancer metastasis
Multicellular circulating tumor cell (CTC) clusters can be up to 50 times more efficient than single CTCs in mediating viable metastasis. Here, combining computational ranking and functional determination, we identify the transmembrane protein Plexin-B2 (PLXNB2) as one of the top molecular targets associated with unfavorable distant metastasis-free survival, showing enriched expression in CTC clusters versus single CTCs from patients with advanced breast cancer (mostly female). Loss of PLXNB2 (Plxnb2) reduces the formation of homotypic tumor cell clusters and heterotypic tumor-myeloid cell clusters, reducing spontaneous metastases in female mice bearing human (mouse) breast cancer. Interactions of PLXNB2 with its ligands SEMA4C on tumor cells and SEMA4A on myeloid cells (monocytes) promote homotypic and heterotypic CTC cluster formation, respectively, thereby driving lung metastasis. Global proteomic analysis reveals downstream effectors of the PLXNB2 pathway associated with tumor cell clustering. Thus, PLXNB2 is a therapeutic target for preventing new metastasis in breast cancer.
Authors
- Lamiaa El-Shennawy (ORCID: https://orcid.org/0000-0001-5705-9220)
- Andrew R. Hoffman (ORCID: https://orcid.org/0000-0002-0145-1917)
- Youbin Zhang
- Reta Birhanu Kitata (ORCID: https://orcid.org/0000-0002-8973-7679)
- Erika K. Ramos (ORCID: https://orcid.org/0000-0003-3194-3442)
- Kalliopi P. Siziopikou (ORCID: https://orcid.org/0000-0002-8689-5508)
- David P. Sullivan (ORCID: https://orcid.org/0000-0002-7462-3898)
- Hannah F. Almubarak (ORCID: https://orcid.org/0000-0001-5895-9968)
- Massimo Cristofanilli (ORCID: https://orcid.org/0000-0002-4194-7175)
- Ami N. Shah (ORCID: https://orcid.org/0000-0003-1347-3782)
- William A. Müller (ORCID: https://orcid.org/0000-0002-4802-2757)
- Rong Xu (ORCID: https://orcid.org/0000-0003-3127-4795)
- Leonidas C. Platanias (ORCID: https://orcid.org/0000-0002-9740-7573)
- Yuzhi Jia (ORCID: https://orcid.org/0000-0002-6534-0036)
- Valery Adorno-Cruz (ORCID: https://orcid.org/0000-0003-0367-8768)
- Rokana Taftaf (ORCID: https://orcid.org/0000-0003-0864-3177)
- Carolina Reduzzi (ORCID: https://orcid.org/0000-0003-0514-0152)
- David Scholten (ORCID: https://orcid.org/0000-0002-4604-1620)
- Emma J. Schuster (ORCID: https://orcid.org/0000-0003-2866-6317)
- Chia‐Feng Tsai (ORCID: https://orcid.org/0000-0002-6514-6911)
- Tujin Shi (ORCID: https://orcid.org/0000-0002-5592-3588)
- William J. Gradishar (ORCID: https://orcid.org/0000-0002-2772-3140)
- Nurmaa K. Dashzeveg (ORCID: https://orcid.org/0000-0002-6702-5187)
- Allegra C. Minor
- Sabina Spahija
- Tong Zhang (ORCID: https://orcid.org/0000-0003-1036-7060)
- Chunlei Zheng
- Huiping Liu (ORCID: https://orcid.org/0000-0003-4822-7995)
- Golam Kibria
- Fangjia Tong
- Joshua R Squires
- William Purev-Ochir
Institutions
- Northwestern University (US)
- Pacific Northwest National Laboratory (US)
- Art Institute of Chicago (US)
- Cornell University (US)
- Chan Zuckerberg Initiative (United States) (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
- Case Western Reserve University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-16
- DOI
- https://doi.org/10.1038/s41467-025-62862-z
- Citations
- 4
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- U.S. Department of Defense
- Breast Cancer Research Foundation
- Northwestern University
- National Institutes of Health
- Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
- National Cancer Institute
- Pacific Northwest National Laboratory