Schuster Emma, Dashzeveg Nurmaa K, Tong Fangjia, Jia Yuzhi, El-Shennawy Lamiaa, Zhang Tong, Hoffman Andrew D, Kitata Reta Birhanu, Kibria Golam, Zhang Youbin, Squires Joshua R, Zheng Chunlei, Ramos Erika, Taftaf Rokana, Scholten David, Almubarak Hannah F, Adorno-Cruz Valery, Sullivan David P, Reduzzi Carolina, Minor Allegra C, Purev-Ochir William, Spahija Sabina, Xu Rong, Siziopikou Kalliopi P, Platanias Leonidas C, Shah Ami, Muller William A, Gradishar William J, Cristofanilli Massimo, Tsai Chia-Feng, Shi Tujin, Liu Huiping
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Driskill Graduate Program in the Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nat Commun. 2025 Aug 16;16(1):7649. doi: 10.1038/s41467-025-62862-z.
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.
多细胞循环肿瘤细胞（CTC）簇在介导活细胞转移方面的效率可比单个CTC高50倍。在此，我们结合计算排序和功能测定，确定跨膜蛋白丛状蛋白-B2（PLXNB2）是与不良无远处转移生存期相关的首要分子靶点之一，在晚期乳腺癌（大多为女性）患者的CTC簇中表达高于单个CTC。PLXNB2（Plxnb2）缺失会减少同型肿瘤细胞簇和异型肿瘤-髓样细胞簇的形成，减少携带人（小鼠）乳腺癌的雌性小鼠的自发转移。PLXNB2与其在肿瘤细胞上的配体SEMA4C以及在髓样细胞（单核细胞）上的配体SEMA4A相互作用，分别促进同型和异型CTC簇的形成，从而驱动肺转移。全局蛋白质组分析揭示了与肿瘤细胞聚集相关的PLXNB2途径的下游效应器。因此，PLXNB2是预防乳腺癌新转移的治疗靶点。
