Mucin5AC promotes breast cancer brain metastasis through cMET/CD44v6.

IF 10 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2025-01-06 DOI:10.1158/1078-0432.CCR-24-1977

Shailendra Kumar Maurya, Jenny A Jaramillo-Gomez, Asad Ur Rehman, Shailendra Kumar Gautam, Mahek Fatima, Md Arafat Khan, Mohd Ali Abbas Zaidi, Parvez Khan, Laiba Anwar, Zahraa Wajih Alsafwani, Ranjana K Kanchan, Sameer Mohiuddin, Ramesh Pothuraju, Raghupathy Vengoji, Ramakanth Chirravuri Venkata, Gopalakrishnan Natarajan, Rakesh Bhatia, Pranita Atri, NaveenKumar Perumal, Sanjib Chaudhary, Imayavaramban Lakshmanan, Sidharth Mahapatra, Geoffrey A Talmon, Jesse L Cox, Lynette M Smith, Juan A Santamaria-Barria, Apar Kishor Ganti, Jawed Akhtar Siddiqui, Diana M Cittelly, Surinder Kumar Batra, Mohd Wasim Nasser

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引用次数: 0

Abstract

Purpose: Breast cancer (BC) brain metastasis (BrM) remains a significant clinical problem. Mucins have been implicated in metastasis; however, if they are also involved in BCBrM remains unknown. We queried BrM patient databases and found Mucin 5AC (MUC5AC) to be upregulated and therefore sought to define the role of MUC5AC in BCBrM.

Experimental design: In-silico dataset analysis, RNA-sequence profiling on patients and cell lines, analysis of patients' serum samples, and in-vitro/vivo knockdown experiments were performed to determine the function of MUC5AC in BCBrM. Coimmunoprecipitation unravels the interactions that can be therapeutically targeted.

Results: Global in-silico transcriptomic analysis showed that MUC5AC is significantly higher in BCBrM patients. Archived BCBrM tissue analysis further revealed significantly higher expression of MUC5AC in all BC subtypes, and high MUC5AC expression predicted poor survival in HER2+ BCBrM. We validated these observations in BCBrM cell lines and tissue samples. Interestingly, elevated levels of MUC5AC were detected in the sera of BCBrM patients. MUC5AC silencing in BCBrM cells reduced migration, adhesion, and reduced BrM in experimental intracardiac injection mouse model. We found high expression of cMET and CD44v6 in BCBrM, which increased MUC5AC expression via HGF signaling. MUC5AC interacts with cMET and CD44v6, suggesting that MUC5AC promotes BCBrM via the cMET/CD44v6 axis. This axis can be targeted with c-MET inhibitor Bozitinib (PLB1001) to inhibit BCBrM.

Conclusions: Our study establishes that the MUC5AC/cMET/CD44v6 axis is critical for BCBrM, and blocking this axis will be a novel therapeutic approach for BCBrM.

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.