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MRNA-seq to test effect of PYK2 inhibitor (defactinib) on LPS induced gene expression in WT and IRF5-/- BMDMs

ABSTRACT: To investigate the specificity of Defactinib on IRF5 target genes we compare LPS-induced transcriptomes in WT and IRF5 KO BMDMs treated with either Defactinib or vehicle. Macrophage transcriptomic signature under PYK2 inhibition phenocopied IRF5 deficiency

ORGANISM(S): Mus musculus

PROVIDER: GSE141082 | GEO | 2021/10/22

REPOSITORIES: GEO

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mRNA-seq to test effect of PYK2 inhibitor (defactinib) on LPS induced gene expression in WT and IRF5-/- BMDMs

Project description:mRNA-seq to test effect of PYK2 inhibitor (defactinib) on LPS induced gene expression in WT and IRF5-/- BMDMs

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Protein-tyrosine kinase 2-beta activates Interferon Regulatory Factor 5 to control inflammation

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Project description:Genetic variants in IRF5 are associated with multiple immune-mediated diseases. IRF5 has been predominantly focused on for its regulation of myeloid-derived cells. We found that IRF5 contributes to CD4+ T cell outcomes and that it regulates early T cell receptor-initiated signaling and subsequently translocates to the nucleus where it binds to promoters of various genes regulated with T cell activation. We report the chromatin state of freshly isolated and activated IRF5+/+ and IRF5-/- CD4+ T cells in vitro. While there are minimal differential peaks between freshly isolated IRF5+/+ and IRF5-/- CD4+ T cells, once activated multiple differential peaks are observed between IRF5+/+ and IRF5-/- CD4+ T cells.

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RNA-sequencing of IRF5+ and IRF5- circulating monocytes from patients with Type-2 Diabetes

Project description:Purpose: To characterise the transcriptomic landscape in monocytes associated with IRF5 expression Methods: RNA sequencing from FACS sorted IRF5+ and IRF5- CD14+ monocytes Results: Differential expression based on IRF5 postiivity provides insight into its roles in monocyte function and in type-2 diabetes Conclusions: This study represents the first analyses of IRF5-dependent transcriptome in circulating monocytes from patients with Type-2 diabetes

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Kinetics of LPS induction in wt and Cop1-ko BMDMs

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Project description:Cancer stem cells (CSCs) are implicated in tumor initiation, metastasis and drug resistance, and are considered as attractive targets for cancer therapy. We identified a clinically relevant signaling nexus mediated by PYK2 and its impact on stemness in triple negative breast cancer (TNBC). PYK2 depletion in multiple mesenchymal TNBC cell lines markedly reduced the expression of PKCα and AXL proteins and reduced the number of mammosphere-forming cells and cells harboring CSCs characteristic markers. PYK2 and PKCα cooperate at a convergence point of multiple stemness-inducing pathways to regulate AXL levels and concomitantly the levels/activation of key transcription factors implicated in stemness including STAT3, TAZ, FRA1 and SMAD3 as well as the pluripotent transcription factors Nanog and Oct4, and in-turn affect their target genes. Targeting the AXL-PYK2-PKCα circuit could be a promising strategy to eliminate CSCs in TNBC and possibly overcome drug resistance.

2021-03-26 | GSE166609 | GEO

Expression analysis of murine splenic B-cells after retroviral transduction with a constitutively active variant of IRF5 (IRF5-4D)

Project description:Genome-wide gene expression analysis of murine splenic B-cells following retroviral transduction with a constitutively active IRF5 (IRF5-4D) Illumina WG-6 v2.0 arrays were hybridized to determine the gene expression profile of murine splenic B-cells following retroviral transduction with i) control virus (MSCV-IRES-CFP) or ii) IRF5-4D virus (MSCV-IRF5-4D-CFP). All hybridizations were done in biological triplicates.

2014-09-24 | E-GEOD-51719 | biostudies-arrayexpress

Mouse modeling dissecting macrophage-breast cancer communication uncovered roles of PYK2 in macrophage recruitment and breast tumorigenesis

Project description:Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. Here we used different genetic mouse models and show that ablation of the tyrosine kinase PYK2, either in breast cancer cells, only in the tumor microenvironment, or both, markedly reduced the number of infiltrating tumor macrophages and concomitantly inhibited tumor angiogenesis and tumor growth. Strikingly, PYK2 depletion only in macrophages was sufficient to induce similar effects. These phenotypic changes were associated with reduced monocyte recruitment and a substantial decrease in tumor-associated macrophages (TAMs). Mechanistically, we show that PYK2 mediates mutual communication between breast cancer cells and macrophages through critical effects on key receptor signaling. Specifically, PYK2 ablation inhibited Notch1 signaling and consequently reduced CCL2 secretion by breast cancer cells, and concurrently reduced the levels of CCR2, CXCR4, IL4R, and Stat6 activation in macrophages. These bidirectional effects modulate monocyte recruitment, macrophage polarization and tumor angiogenesis. PYK2 expression is correlated with infiltrated macrophages in breast cancer patients, and its significant effects on macrophage infiltration and their pro-tumorigenic phenotype suggest that PYK2 targeting can be utilized as an effective strategy to modulate TAMs and possibly sensitize breast cancer to immunotherapy.

2022-02-09 | GSE193168 | GEO

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