Lateral interactions between B7-H3 and CD147 are essential for stemness in breast cancer: a novel insight from proximal proteome analysis

Oncogenic cell-surface membrane proteins contribute to the phenotypic and functional characteristics of cancer stem cells (CSCs). We quantitatively analyzed cell-surface membrane proteins that are in close proximity to CD147 in CSCs using proximity-labeling proteomic approach. Moreover, we compared CSCs to non-CSCs to identify CSC-specific cell-surface membrane proteins that are the nearest neighbors of CD147 and revealed that lateral interaction between CD147 and CD276 (B7H3) concealed within the lipid raft microdomain in CSCs confers resistance to docetaxel, known to treat many types of cancer patients including metastatic breast cancer. Furthermore, we found that co-expression of CD147 and CD276 in patients with HER2+ breast cancer who received chemotherapy had poor disease-free survival (DFS) and Overall survival (OS) rates (p = 0.04 and 0.08, respectively). Subsequent immunohistochemical analysis indicated that co-expression of CD147 and CD276 may be associated with poor response to chemotherapy in an independent HER2+ BC cohort. Altogether, our study suggests that the lateral interaction between CD147 and its proximal partners, such as CD276, may be related to a poor prognostic factor in BC and a predictive marker for the critical phenotypic determinant of breast cancer stemness.

致癌性细胞表面膜蛋白可调控癌症干细胞（cancer stem cells, CSCs）的表型与功能特征。本研究采用邻近标记蛋白质组学方法，对癌症干细胞中与CD147紧密邻近的细胞表面膜蛋白进行了定量分析。此外，本研究通过对比癌症干细胞与非癌症干细胞，筛选得到CD147的癌症干细胞特异性邻近细胞表面膜蛋白，并揭示出：在癌症干细胞的脂质筏微区中，CD147与CD276（B7H3）的侧向相互作用可赋予细胞对多西他赛的耐药性；多西他赛是一款可用于治疗包括转移性乳腺癌在内的多种恶性肿瘤的临床化疗药物。进一步研究发现，在接受化疗的HER2阳性乳腺癌患者中，CD147与CD276共表达的患者无病生存期（disease-free survival, DFS）与总生存期（overall survival, OS）均较差（分别对应p=0.04与p=0.08）。后续免疫组化分析显示，在一项独立的HER2阳性乳腺癌（breast cancer, BC）队列中，CD147与CD276的共表达可能与化疗应答不佳相关。综上，本研究表明，CD147与其邻近互作蛋白（如CD276）之间的侧向相互作用，可能是乳腺癌的不良预后因素，同时可作为乳腺癌干细胞干性关键表型特征的预测标志物。