PXD058906-1

PXD058906 is an original dataset announced via ProteomeXchange.

Title	MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts
Description	Breast cancer-associated-fibroblasts (bCAFs) consist of two pro-tumoral populations: inflammatory CAFs (iCAF) releasing pro-inflammatory cytokines, and myofibroblastic CAFs (myCAF) known for their extensive production of extracellular matrix proteins and immunosuppressive features. We have previously shown that targeting the anti-apoptotic protein MCL-1 in primary culture of bCAFs directly derived from human samples reduces their myofibroblastic characteristics linked to actomyosin cytoskeleton disorganization and mitochondrial fragmentation. In this study, we explore the involvement of this protein in phenotypic differentiation and plasticity of bCAFs. Single-cell RNA-sequencing analysis reveals a shift from wound-myCAF to IL-iCAFs phenotype expressing genes involved in inflammation like IL-8, IL-1β, CXCL1, CXCL3, CCL2 and in angiogenesis like VEGF after MCL-1 gene silencing in bCAFs. In vitro, targeting of MCL-1 in bCAFs induces an increase of VEGF secretion associated with enhanced endothelial cell tubulogenesis. In ovo, using chicken chorioallantoic membrane model, we engrafted breast cancer cells and bCAFs to study vascularization. Our data suggest that a low level of MCL-1 expression in bCAF is associated with greater peritumoral vascular density in a VEGF-dependent manner. Furthermore, chemotherapy that downregulated MCL-1 expression in bCAFs is accompanied by the same pro-angiogenic effects. Mechanistically, pharmacological inhibition of MCL-1 promotes mitochondrial outer membrane permeabilization and NF-κB activation in cGAS-STING independent-manner. Blockage of NF-κB activity with an IKKβ inhibitor counteracts VEGF and pro-inflammatory factors transcription induced by MCL-1 inhibition in bCAFs. Our findings highlight a novel role for MCL-1 in regulating the pro-angiogenic properties of bCAFs, and provide new elements for characterizing the different bCAFs subpopulations.
HostingRepository	PRIDE
AnnounceDate	2025-08-14
AnnouncementXML	Submission_2025-08-14_01:58:54.414.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	François Guillonneau
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-16 05:30:38	ID requested
⏵ 1	2025-08-14 01:58:54	announced

10.1038/S41419-025-07920-6;

submitter keyword: cancer-associated fibroblast, human breast cancer,LC-MS, microenvironment, angiogenesis, mitochondria, apoptosis

Frédérique Souazé
contact affiliation	Université de Nantes, INSERM, CNRS, CRCI2NA, F-44000 Nantes, France
contact email	frederique.souaze@univ-nantes.fr
lab head
François Guillonneau
contact affiliation	Institut de Cancerologie de l'Ouest (ICO) Angers
contact email	francois.guillonneau@inserm.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058906
     1. Label: PRIDE project
     2. Name: MCL-1 as a molecular switch between myofibroblastic and pro-angiogenic features of breast cancer-associated fibroblasts