Effect of MCL-1 antagonist in breast cancer associated fibroblasts
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA868690 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21012447.fastq.gz | Fastqsanger.gz | |||
| SRR21012448.fastq.gz | Fastqsanger.gz | |||
| SRR21012449.fastq.gz | Fastqsanger.gz | |||
| SRR21012450.fastq.gz | Fastqsanger.gz | |||
| SRR21012451.fastq.gz | Fastqsanger.gz |
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Project description: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 co-culture 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.
2022-08-14 | GSE211012 | GEO
Project 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.
2025-08-14 | PXD058906 | Pride
Project 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.
2025-08-13 | GSE299144 | GEO
Project description:The expression of TWEAK and Fn14 was increased in early skin lesions of SSc patients. Fn14 expression on human dermal fibroblasts is significantly increased after stimulation with serum from patients with systemic sclerosis. The interplay between TWEAK and Fn14 is pivotal in the fibrotic progression of various autoimmune diseases. These observations implicate the TWEAK/Fn14 signaling pathway may as a critical player in the pathological advancement of systemic sclerosis; however, the precise underlying mechanisms require further clarification. Thus, human dermal fibroblasts were stimulated by serum from systemic sclerosis patients, and with or without the addition of Fn14 antagonists. We then assessed the antifibrotic effects of this antagonist through RNA sequencing, and preliminary exploration of possible molecular mechanisms.
2024-08-05 | GSE273556 | GEO
Project description:Cancer Associated Fibroblasts (CAF) are a dominant and critical cell type of the tumour microenvironment and can lead to breast cancer progression. TGF-β has been reported to influence fibroblast to myofibroblast activation, which is similar to cancer associated fibroblast phenotype. To understand the mechanism of TGF-β mediated CAF phenotype, we have performed a comparative proteomic analysis of conditioned media from CAF (isolated from breast cancer biopsy tissues) and normal mammary fibroblasts engineered to over-express TGF-β1. Liquid chromatography/ tandem mass spectrometry (LC ESI Q-TOF-MS/MS) assay of conditioned media and Venn analysis of the acquired data, revealed approximately 185 common proteins secreted by the three fibroblast types (CAF, normal mammary fibroblasts and TGF-β over expressing mammary fibroblasts). Among these, 12 proteins exclusively overlap between normal fibroblasts and CAF and 20 proteins exclusively overlap between CAF and TGF-β1 over-expressing fibroblasts. This analysis reveals interesting targets which may be important in activation phenotype of CAF and breast cancer progression.
2025-08-26 | PXD022374 | Pride
Project description:Disruption of mitochondrial integrity induced by MCL-1 targeting enhances the pro-angiogenic phenotype of breast cancer-associated fibroblasts
| PRJNA1272841 | ENA
Project description:To determine the global transcriptome changes in mantle cell lymphoma cells following treatment with the BET bromodomain antagonist, JQ1 Mantle Cell Lymphoma (MCL) cells exhibit increased B cell receptor and NFkB activities. The BET protein BRD4 is essential for the transcriptional activity of NFkB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and CDK4/6, inhibits the nuclear RelA levels and the expression of NFκB target genes including Brutonâs Tyrosine Kinase (BTK) in MCL cells. While lowering the levels of the anti-apoptotic BCL2 family proteins, BA treatment induces the pro-apoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Co-treatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared to each agent alone, co-treatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells which overexpress CDK6, BCL2, Bcl-xL, XIAP and AKT, but lack ibrutinib resistance-conferring BTK mutation. Co-treatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. MO2058 cells treated with vehicle, 250 nM or 1000 nM JQ1 for 8 hours. Samples were acquired and analyzed in duplicate.
2015-12-31 | E-GEOD-70651 | biostudies-arrayexpress
Project description:To determine the global transcriptome changes in mantle cell lymphoma cells following treatment with the BET bromodomain antagonist, JQ1 Mantle Cell Lymphoma (MCL) cells exhibit increased B cell receptor and NFkB activities. The BET protein BRD4 is essential for the transcriptional activity of NFkB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and CDK4/6, inhibits the nuclear RelA levels and the expression of NFκB target genes including Bruton’s Tyrosine Kinase (BTK) in MCL cells. While lowering the levels of the anti-apoptotic BCL2 family proteins, BA treatment induces the pro-apoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Co-treatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared to each agent alone, co-treatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells which overexpress CDK6, BCL2, Bcl-xL, XIAP and AKT, but lack ibrutinib resistance-conferring BTK mutation. Co-treatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL.
2015-12-31 | GSE70651 | GEO
Project description:Transcriptional profiling of the human breast cancer cells and primary breast cancer-associated fibroblasts exposed to compressive stress. Four subtypes of breast cancer cells (BT-474, MCF7, SK-BR-3, MDA-MB-231) and four cases of primary breast cancer-associated fibroblasts (CAF1, CAF2, CAF3, and CAF4) were exposed to a static compressive stress for 24 h.
2019-06-22 | GSE133134 | GEO
Project description:Breast cancer is still the most common type of cancer in women; an important role in carcinogenesis is actually attributed to cancer-associated fibroblasts. In this study we investigated whether it is possible to assess the functional state of cancer-associated fibroblasts through tumor tissue proteome profiling. Tissue proteomics was performed on tumor-central, tumor-near and tumor-distant biopsy sections from breast adenocarcinoma patients, which allowed us to identify 2074 proteins. Data were interpreted referring to reference proteome profiles generated from primary human mammary fibroblasts comprising 4095 proteins. These cells were analyzed in quiescent cell state, as well as after in vitro treatment with TGFβ or IL-1β, stimulating wound healing or inflammatory processes, respectively. Representative for cancer cells, we investigated the mammary carcinoma cell line ZR-75-1, identifying 5212 proteins. Comparison of tissue proteomics data with all those reference profiles revealed predominance of cancer cell-derived proteins within the tumor and fibroblast-derived proteins in the tumor-distant tissue sections. Remarkably, proteins characteristic for acute inflammation were hardly identified in the tissue samples. In contrast, several proteins found by us to be induced by TGFβ in mammary fibroblasts, including fibulin-5, SLC2A1 and MUC18, were positively identified in all tissue samples, with relatively higher abundance in tumor neighboring tissue sections. These findings indicate a predominance of cancer-associated fibroblasts with wound healing activities localized around tumors.
2014-09-23 | PXD001311 | Pride