Computational ranking identifies Plexin-B2 in circulating tumor cell clustering with monocytes in breast cancer metastasis
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.
Article Details
Authors (32)
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
Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
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
Weill-Cornell Medicine, New York–Presbyterian Hospital, New York
Chia-Feng Tsai
Tujin Shi
Huiping Liu