Shailendra Kumar Maurya, Jenny A Jaramillo-Gómez, 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
{"title":"Mucin5AC通过cMET/CD44v6促进乳腺癌脑转移。","authors":"Shailendra Kumar Maurya, Jenny A Jaramillo-Gómez, 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","doi":"10.1158/1078-0432.CCR-24-1977","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Experimental design: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"921-935"},"PeriodicalIF":10.0000,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882111/pdf/","citationCount":"0","resultStr":"{\"title\":\"Mucin 5AC Promotes Breast Cancer Brain Metastasis through cMET/CD44v6.\",\"authors\":\"Shailendra Kumar Maurya, Jenny A Jaramillo-Gómez, 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\",\"doi\":\"10.1158/1078-0432.CCR-24-1977\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Experimental design: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":10279,\"journal\":{\"name\":\"Clinical Cancer Research\",\"volume\":\" \",\"pages\":\"921-935\"},\"PeriodicalIF\":10.0000,\"publicationDate\":\"2025-03-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882111/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1078-0432.CCR-24-1977\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.CCR-24-1977","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Mucin 5AC Promotes Breast Cancer Brain Metastasis through cMET/CD44v6.
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.
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.
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