Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition
CD146, also known as melanoma cell adhesion molecule (MCAM), is expressed in numerous cancers and has been implicated in the regulation of metastasis. We show that CD146 negatively regulates transendothelial migration (TEM) in breast cancer. This inhibitory activity is reflected by a reduction in MC...
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| Format: | Article |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1129015/full |
| _version_ | 1797845342981455872 |
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| author | Aarren J. Mannion Adam F. Odell Syed Murtuza Baker Laura C. Matthews Pamela F. Jones Graham P. Cook |
| author_facet | Aarren J. Mannion Adam F. Odell Syed Murtuza Baker Laura C. Matthews Pamela F. Jones Graham P. Cook |
| author_sort | Aarren J. Mannion |
| collection | DOAJ |
| description | CD146, also known as melanoma cell adhesion molecule (MCAM), is expressed in numerous cancers and has been implicated in the regulation of metastasis. We show that CD146 negatively regulates transendothelial migration (TEM) in breast cancer. This inhibitory activity is reflected by a reduction in MCAM gene expression and increased promoter methylation in tumour tissue compared to normal breast tissue. However, increased CD146/MCAM expression is associated with poor prognosis in breast cancer, a characteristic that is difficult to reconcile with inhibition of TEM by CD146 and its epigenetic silencing. Single cell transcriptome data revealed MCAM expression in multiple cell types, including the malignant cells, tumour vasculature and normal epithelium. MCAM expressing malignant cells were in the minority and expression was associated with epithelial to mesenchymal transition (EMT). Furthermore, gene expression signatures defining invasiveness and a stem cell-like phenotype were most strongly associated with mesenchymal-like tumour cells with low levels of MCAM mRNA, likely to represent a hybrid epithelial/mesenchymal (E/M) state. Our results show that high levels of MCAM gene expression are associated with poor prognosis in breast cancer because they reflect tumour vascularisation and high levels of EMT. We suggest that high levels of mesenchymal-like malignant cells reflect large populations of hybrid E/M cells and that low CD146 expression on these hybrid cells is permissive for TEM, aiding metastasis. |
| first_indexed | 2024-04-09T17:37:29Z |
| format | Article |
| id | doaj.art-91b1642de92d457a99a0a2a29369437a |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-09T17:37:29Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-91b1642de92d457a99a0a2a29369437a2023-04-17T13:49:10ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-04-011110.3389/fcell.2023.11290151129015Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transitionAarren J. Mannion0Adam F. Odell1Syed Murtuza Baker2Laura C. Matthews3Pamela F. Jones4Graham P. Cook5Leeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United KingdomLeeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United KingdomFaculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, United KingdomLeeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United KingdomLeeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United KingdomLeeds Institute of Medical Research, University of Leeds School of Medicine, St. James’s University Hospital, Leeds, United KingdomCD146, also known as melanoma cell adhesion molecule (MCAM), is expressed in numerous cancers and has been implicated in the regulation of metastasis. We show that CD146 negatively regulates transendothelial migration (TEM) in breast cancer. This inhibitory activity is reflected by a reduction in MCAM gene expression and increased promoter methylation in tumour tissue compared to normal breast tissue. However, increased CD146/MCAM expression is associated with poor prognosis in breast cancer, a characteristic that is difficult to reconcile with inhibition of TEM by CD146 and its epigenetic silencing. Single cell transcriptome data revealed MCAM expression in multiple cell types, including the malignant cells, tumour vasculature and normal epithelium. MCAM expressing malignant cells were in the minority and expression was associated with epithelial to mesenchymal transition (EMT). Furthermore, gene expression signatures defining invasiveness and a stem cell-like phenotype were most strongly associated with mesenchymal-like tumour cells with low levels of MCAM mRNA, likely to represent a hybrid epithelial/mesenchymal (E/M) state. Our results show that high levels of MCAM gene expression are associated with poor prognosis in breast cancer because they reflect tumour vascularisation and high levels of EMT. We suggest that high levels of mesenchymal-like malignant cells reflect large populations of hybrid E/M cells and that low CD146 expression on these hybrid cells is permissive for TEM, aiding metastasis.https://www.frontiersin.org/articles/10.3389/fcell.2023.1129015/fullCD146MCAMtransendothelial migration (TEM)epithelial mesenchymal transition (EMT)breast cancermetastasis |
| spellingShingle | Aarren J. Mannion Adam F. Odell Syed Murtuza Baker Laura C. Matthews Pamela F. Jones Graham P. Cook Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition Frontiers in Cell and Developmental Biology CD146 MCAM transendothelial migration (TEM) epithelial mesenchymal transition (EMT) breast cancer metastasis |
| title | Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition |
| title_full | Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition |
| title_fullStr | Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition |
| title_full_unstemmed | Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition |
| title_short | Pro- and anti-tumour activities of CD146/MCAM in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition |
| title_sort | pro and anti tumour activities of cd146 mcam in breast cancer result from its heterogeneous expression and association with epithelial to mesenchymal transition |
| topic | CD146 MCAM transendothelial migration (TEM) epithelial mesenchymal transition (EMT) breast cancer metastasis |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1129015/full |
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