Targeting of MCL-1 in breast cancer-associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties
| Autor: | Thomas L. Bonneaud, Chloé C. Lefebvre, Lisa Nocquet, Agnes Basseville, Julie Roul, Hugo Weber, Mario Campone, Philippe P. Juin, Frédérique Souazé |
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| Přispěvatelé: | Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), SIRIC ILIAD [Angers, Nantes], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC René Gauducheau, Ligue contre le cancer (CD53, CD22, CD44), SIRIC ILIAD, INCa-DGOS Inserm-12558, and INCa-PLBio 16086, Souazé, Frédérique |
| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
[SDV]Life Sciences [q-bio] Immunology Breast Neoplasms Cell Biology Apoptosis / drug effects Mitochondria dynamic [SDV] Life Sciences [q-bio] Cellular and Molecular Neuroscience Phenotype Breast cancer Cancer associated fibroblasts CAFs Cancer-Associated Fibroblasts Humans Myeloid Cell Leukemia Sequence 1 Protein Female MCL-1 Ecosystem |
| Zdroj: | Cell Death and Disease Cell Death and Disease, 2022, 13 (9), pp.787. ⟨10.1038/s41419-022-05214-9⟩ |
| ISSN: | 2041-4889 |
| Popis: | Cancer-associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFs) typically express MCL-1. We show here that pharmacological inhibition or knock down of this regulator of mitochondrial integrity in primary bCAFs directly derived from human samples mitigates myofibroblastic features. This decreases expression of genes involved in actomyosin organization and contractility (associated with a cytoplasmic retention of the transcriptional regulator, yes-associated protein—YAP) and decreases bCAFs ability to promote cancer cells invasion in 3D coculture assays. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve. Mechanistically, pharmacological inhibition of MCL-1 with a specific BH3 mimetic promotes mitochondrial fragmentation in bCAFs. Inhibition of the mitochondrial fission activity of DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment, allows the maintenance of the myofibroblastic phenotype of bCAFs. |
| Databáze: | OpenAIRE |
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