Computational ranking identifies Plexin-B2 in circulating tumor cell clustering with monocytes in breast cancer metastasis

Emma Schuster, Nurmaa K. Dashzeveg, Fangjia Tong, Yuzhi Jia, Lamiaa El-Shennawy, Tong Zhang, Andrew D. Hoffman, Reta Birhanu Kitata, Golam Kibria, Youbin Zhang, Joshua R. Squires, Chunlei Zheng, Erika Ramos, Rokana Taftaf, David Scholten, Hannah F. Almubarak, Valery Adorno-Cruz, David P. Sullivan, Carolina Reduzzi, Allegra C. Minor, William Purev-Ochir, Sabina Spahija, Rong Xu, Kalliopi P. Siziopikou, Leonidas C. Platanias, Ami Shah, William A. Muller, William J. Gradishar, Massimo Cristofanilli, Chia-Feng Tsai, Tujin Shi () and Huiping Liu ()
Additional contact information
Emma Schuster: Northwestern University Feinberg School of Medicine
Nurmaa K. Dashzeveg: Northwestern University Feinberg School of Medicine
Fangjia Tong: Northwestern University Feinberg School of Medicine
Yuzhi Jia: Northwestern University Feinberg School of Medicine
Lamiaa El-Shennawy: Northwestern University Feinberg School of Medicine
Tong Zhang: Pacific Northwest National Laboratory
Andrew D. Hoffman: Northwestern University Feinberg School of Medicine
Reta Birhanu Kitata: Pacific Northwest National Laboratory
Golam Kibria: Northwestern University Feinberg School of Medicine
Youbin Zhang: Northwestern University Feinberg School of Medicine
Joshua R. Squires: Northwestern University Feinberg School of Medicine
Chunlei Zheng: Case Western Reserve University
Erika Ramos: Northwestern University Feinberg School of Medicine
Rokana Taftaf: Northwestern University Feinberg School of Medicine
David Scholten: Northwestern University Feinberg School of Medicine
Hannah F. Almubarak: Northwestern University Feinberg School of Medicine
Valery Adorno-Cruz: Northwestern University Feinberg School of Medicine
David P. Sullivan: Northwestern University Feinberg School of Medicine
Carolina Reduzzi: Weill Cornell School of Medicine
Allegra C. Minor: Northwestern University Feinberg School of Medicine
William Purev-Ochir: Northwestern University Feinberg School of Medicine
Sabina Spahija: Northwestern University Feinberg School of Medicine
Rong Xu: Case Western Reserve University
Kalliopi P. Siziopikou: Northwestern University Feinberg School of Medicine
Leonidas C. Platanias: Northwestern University Feinberg School of Medicine
Ami Shah: Northwestern University Feinberg School of Medicine
William A. Muller: Northwestern University Feinberg School of Medicine
William J. Gradishar: Northwestern University Feinberg School of Medicine
Massimo Cristofanilli: Weill Cornell School of Medicine
Chia-Feng Tsai: Pacific Northwest National Laboratory
Tujin Shi: Pacific Northwest National Laboratory
Huiping Liu: Northwestern University Feinberg School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62862-z

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