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Disruption of mitochondrial integrity induced by MCL-1 targeting enhances the pro-angiogenic phenotype of breast cancer-associated fibroblasts

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299144 | GEO | 2025/08/13

REPOSITORIES: GEO

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Project description:ABSTRACT Background: Human breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes – the other being interlobular fibroblasts. While cancer associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship – if any - with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs), and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation. Methods: Primary breast tumor derived CAFs were transduced to express human telomerase reverse transcriptase (hTERT) and sorted into CD105low and CD105high populations using fluorescence activated cell sorting (FACS). The two populations were tested for differentiation similarities to iCAF and myCAF states through transcriptome-wide RNA-Sequencing (RNA-Seq) including comparison to an available iCAF-myCAF cell state atlas. Inference of origin in interlobular and lobular fibroblasts relied on RNA-seq profiles, immunocytochemistry and growth characteristics. Osteogenic differentiation and bone formation assays in culture and in vivo were employed to gauge for origin in bone marrow mesenchymal stem cells (bMSCs). Functional characteristics were assessed with respect to contractility in culture and interaction with tumor cells in mouse xenografts. The cells’ gene expression signatures were tested for association with clinical outcome of breast cancer patients using survival data in The Cancer Genome Atlas database (TCGA). Results: We demonstrate that iCAFs have properties in common with interlobular fibroblasts while myCAFs and lobular fibroblasts are related. None of the CAFs qualify as bMSCs as revealed by lack of critical performance in bone formation assays. Functionally, myCAFs and lobular fibroblasts are almost equally tumor promoting as opposed to iCAFs and interlobular fibroblasts. A myCAF gene signature is found to associate with poor breast cancer specific survival. Conclusions: We propose that iCAFs and myCAFs originate in interlobular and lobular fibroblasts, respectively, and more importantly, that the tumor promoting properties of lobular fibroblasts renders the TDLU an epicenter for breast cancer evolution.

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Disruption of mitochondrial integrity induced by MCL-1 targeting enhances the pro-angiogenic phenotype of breast cancer-associated fibroblasts

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