黏蛋白5AC通过cMET/CD44v6促进乳腺癌脑转移。
Mucin 5AC Promotes Breast Cancer Brain Metastasis through cMET/CD44v6.
作者信息
Maurya Shailendra Kumar, Jaramillo-Gómez Jenny A, Rehman Asad Ur, Gautam Shailendra Kumar, Fatima Mahek, Khan Md Arafat, Zaidi Mohd Ali Abbas, Khan Parvez, Anwar Laiba, Alsafwani Zahraa Wajih, Kanchan Ranjana K, Mohiuddin Sameer, Pothuraju Ramesh, Vengoji Raghupathy, Chirravuri Venkata Ramakanth, Natarajan Gopalakrishnan, Bhatia Rakesh, Atri Pranita, Perumal NaveenKumar, Chaudhary Sanjib, Lakshmanan Imayavaramban, Mahapatra Sidharth, Talmon Geoffrey A, Cox Jesse L, Smith Lynette M, Santamaria-Barria Juan A, Ganti Apar Kishor, Siddiqui Jawed Akhtar, Cittelly Diana M, Batra Surinder Kumar, Nasser Mohd Wasim
机构信息
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Department of Pathology, University of Colorado Anschutz Medical Campus, University of Colorado Comprehensive Cancer Center, Aurora, Colorado.
出版信息
Clin Cancer Res. 2025 Mar 3;31(5):921-935. doi: 10.1158/1078-0432.CCR-24-1977.
PURPOSE
Breast cancer brain metastasis remains a significant clinical problem. Mucins have been implicated in metastasis; however, whether they are also involved in breast cancer brain metastasis remains unknown. We queried databases of patients with brain metastasis and found mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in breast cancer brain metastasis.
EXPERIMENTAL DESIGN
In silico dataset analysis, RNA-sequence profiling of patient samples and cell lines, analysis of patient serum samples, and in vitro/in vivo knockdown experiments were performed to determine the function of MUC5AC in breast cancer brain metastasis. Coimmunoprecipitation was used to unravel the interactions that can be therapeutically targeted.
RESULTS
Global in silico transcriptomic analysis showed that MUC5AC is significantly higher in patients with breast cancer brain metastasis. Analysis of archived breast cancer brain metastasis tissue further revealed significantly higher expression of MUC5AC in all breast cancer subtypes, and high MUC5AC expression predicted poor survival in HER2+ breast cancer brain metastasis. We validated these observations in breast cancer brain metastatic cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of patients with breast cancer brain metastasis. MUC5AC silencing in breast cancer brain metastatic cells reduced their migration and adhesion in vitro and in brain metastasis in the intracardiac injection mouse model. We found high expression of cMET and CD44v6 in breast cancer brain metastasis, which increased MUC5AC expression via hepatocyte growth factor signaling. In addition, MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes breast cancer brain metastasis via the cMET/CD44v6 axis. Inhibition of the MUC5AC/cMET/CD44v6 axis with the blood-brain barrier-permeable cMET inhibitor bozitinib (PLB1001) effectively inhibits breast cancer brain metastasis.
CONCLUSIONS
Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for breast cancer brain metastasis, and blocking this axis will be a novel therapeutic approach for breast cancer brain metastasis.
目的
乳腺癌脑转移仍然是一个重大的临床问题。黏蛋白与转移有关；然而，它们是否也参与乳腺癌脑转移尚不清楚。我们查询了脑转移患者数据库，发现黏蛋白5AC（MUC5AC）上调，因此试图确定MUC5AC在乳腺癌脑转移中的作用。
实验设计
进行了计算机数据集分析、患者样本和细胞系的RNA序列分析、患者血清样本分析以及体外/体内敲低实验，以确定MUC5AC在乳腺癌脑转移中的功能。采用免疫共沉淀法来揭示可用于治疗靶点的相互作用。
结果
全面的计算机转录组分析表明，MUC5AC在乳腺癌脑转移患者中显著升高。对存档的乳腺癌脑转移组织的分析进一步显示，MUC5AC在所有乳腺癌亚型中的表达均显著更高，且MUC5AC高表达预示着HER2+乳腺癌脑转移患者的生存率较低。我们在乳腺癌脑转移细胞系和组织样本中验证了这些观察结果。有趣的是，在乳腺癌脑转移患者的血清中检测到MUC5AC水平升高。在乳腺癌脑转移细胞中沉默MUC5AC可降低其在体外的迁移和黏附能力以及在心脏内注射小鼠模型中的脑转移能力。我们发现cMET和CD44v6在乳腺癌脑转移中高表达，它们通过肝细胞生长因子信号通路增加MUC5AC的表达。此外，MUC5AC与cMET和CD44v6相互作用，这表明MUC5AC通过cMET/CD44v6轴促进乳腺癌脑转移。使用可透过血脑屏障的cMET抑制剂博西替尼（PLB1001）抑制MUC5AC/cMET/CD44v6轴可有效抑制乳腺癌脑转移。
结论
我们的研究表明，MUC5AC/cMET/CD44v6轴对乳腺癌脑转移至关重要，阻断该轴将是一种治疗乳腺癌脑转移的新方法。
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