MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts
Abstract Breast cancer-associated fibroblasts (bCAFs) comprise inflammatory CAFs (iCAFs), characterized by the secretion of pro-inflammatory cytokines, and myofibroblastic CAFs (myCAFs), distinguished by their high production of extracellular matrix and their immunosuppressive properties. We previou...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07920-6 |
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| author | Chloé C. Lefebvre Philippine Giowachini Jennifer Derrien Maxime Naour Isabelle Corre Laura Thirouard Elise Douillard David Chiron François Guillonneau Lucas Treps Mario Campone Philippe P. Juin Frédérique Souazé |
| author_facet | Chloé C. Lefebvre Philippine Giowachini Jennifer Derrien Maxime Naour Isabelle Corre Laura Thirouard Elise Douillard David Chiron François Guillonneau Lucas Treps Mario Campone Philippe P. Juin Frédérique Souazé |
| author_sort | Chloé C. Lefebvre |
| collection | DOAJ |
| description | Abstract Breast cancer-associated fibroblasts (bCAFs) comprise inflammatory CAFs (iCAFs), characterized by the secretion of pro-inflammatory cytokines, and myofibroblastic CAFs (myCAFs), distinguished by their high production of extracellular matrix and their immunosuppressive properties. We previously showed that targeting the anti-apoptotic protein MCL-1 in primary culture of bCAF derived directly from human samples reduces their myofibroblastic characteristics. We herein show by single-cell RNA-sequencing analysis of bCAFs that MCL-1 knock down induces a phenotypic shift from wound-myCAF to IL-iCAF, characterized by the upregulation of genes associated with inflammation as well as angiogenesis-related genes. In vitro, genetic and pharmacologic MCL-1 inhibition increases VEGF secretion by bCAFs, enhancing endothelial cell tubulogenesis. In a chicken chorioallantoic membrane (CAM) model in ovo, co-engraftment of breast cancer cells and bCAFs with reduced MCL-1 expression leads to heightened peritumoral vascular density, driven by VEGF. Mechanistically, the pro-angiogenic phenotype revealed by MCL-1 inhibition is dependent on BAX-BAK activity. It results in NF-κB activation, inhibition of which by a IKKβ inhibitor suppresses the transcription of VEGF and pro-inflammatory factors triggered by MCL-1 inhibition in bCAFs. Chemotherapy downregulates MCL-1 in bCAFs via an increase of NOXA, the endogenous MCL-1 inhibitor, promoting a pro-angiogenic and inflammatory phenotype through the NOXA/MCL-1/NF-kB axis. Overall, these findings uncover a novel regulatory function of MCL-1 in determining bCAF subpopulation differentiation and highlight its role in modulating their pro-angiogenic properties, in response to treatment in particular. |
| format | Article |
| id | doaj-art-222601868e824ff48e7b56b2cb48fdea |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-222601868e824ff48e7b56b2cb48fdea2025-08-20T03:46:28ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111410.1038/s41419-025-07920-6MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblastsChloé C. Lefebvre0Philippine Giowachini1Jennifer Derrien2Maxime Naour3Isabelle Corre4Laura Thirouard5Elise Douillard6David Chiron7François Guillonneau8Lucas Treps9Mario Campone10Philippe P. Juin11Frédérique Souazé12Université de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NANantes Université, INRAE UMR1280, PhAN, IMADUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAUniversité de Nantes, INSERM, CNRS, CRCI2NAAbstract Breast cancer-associated fibroblasts (bCAFs) comprise inflammatory CAFs (iCAFs), characterized by the secretion of pro-inflammatory cytokines, and myofibroblastic CAFs (myCAFs), distinguished by their high production of extracellular matrix and their immunosuppressive properties. We previously showed that targeting the anti-apoptotic protein MCL-1 in primary culture of bCAF derived directly from human samples reduces their myofibroblastic characteristics. We herein show by single-cell RNA-sequencing analysis of bCAFs that MCL-1 knock down induces a phenotypic shift from wound-myCAF to IL-iCAF, characterized by the upregulation of genes associated with inflammation as well as angiogenesis-related genes. In vitro, genetic and pharmacologic MCL-1 inhibition increases VEGF secretion by bCAFs, enhancing endothelial cell tubulogenesis. In a chicken chorioallantoic membrane (CAM) model in ovo, co-engraftment of breast cancer cells and bCAFs with reduced MCL-1 expression leads to heightened peritumoral vascular density, driven by VEGF. Mechanistically, the pro-angiogenic phenotype revealed by MCL-1 inhibition is dependent on BAX-BAK activity. It results in NF-κB activation, inhibition of which by a IKKβ inhibitor suppresses the transcription of VEGF and pro-inflammatory factors triggered by MCL-1 inhibition in bCAFs. Chemotherapy downregulates MCL-1 in bCAFs via an increase of NOXA, the endogenous MCL-1 inhibitor, promoting a pro-angiogenic and inflammatory phenotype through the NOXA/MCL-1/NF-kB axis. Overall, these findings uncover a novel regulatory function of MCL-1 in determining bCAF subpopulation differentiation and highlight its role in modulating their pro-angiogenic properties, in response to treatment in particular.https://doi.org/10.1038/s41419-025-07920-6 |
| spellingShingle | Chloé C. Lefebvre Philippine Giowachini Jennifer Derrien Maxime Naour Isabelle Corre Laura Thirouard Elise Douillard David Chiron François Guillonneau Lucas Treps Mario Campone Philippe P. Juin Frédérique Souazé MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts Cell Death and Disease |
| title | MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts |
| title_full | MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts |
| title_fullStr | MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts |
| title_full_unstemmed | MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts |
| title_short | MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts |
| title_sort | mcl 1 as a molecular switch between myofibroblastic and pro angiogenic features of breast cancer associated fibroblasts |
| url | https://doi.org/10.1038/s41419-025-07920-6 |
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