Targeting of MCL-1 in breast cancer-associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties.

Autor: Bonneaud TL; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France.; SIRIC ILIAD, Nantes, Angers, France., Lefebvre CC; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France.; SIRIC ILIAD, Nantes, Angers, France., Nocquet L; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France.; SIRIC ILIAD, Nantes, Angers, France., Basseville A; Omics Data Science Unit, ICO, Angers, France., Roul J; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France.; SIRIC ILIAD, Nantes, Angers, France.; ICO René Gauducheau, Saint Herblain, France., Weber H; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France.; SIRIC ILIAD, Nantes, Angers, France., Campone M; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France.; SIRIC ILIAD, Nantes, Angers, France.; ICO René Gauducheau, Saint Herblain, France., Juin PP; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France. philippe.juin@univ-nantes.fr.; SIRIC ILIAD, Nantes, Angers, France. philippe.juin@univ-nantes.fr.; ICO René Gauducheau, Saint Herblain, France. philippe.juin@univ-nantes.fr., Souazé F; Université de Nantes, INSERM, CNRS, CRCI2NA, 44000, Nantes, France. frederique.souaze@univ-nantes.fr.; SIRIC ILIAD, Nantes, Angers, France. frederique.souaze@univ-nantes.fr.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Sep 14; Vol. 13 (9), pp. 787. Date of Electronic Publication: 2022 Sep 14.
DOI: 10.1038/s41419-022-05214-9
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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