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ABSTRACT:
PROVIDER: PRJEB33027 | ENA |
REPOSITORIES: ENA
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Project description:The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. Specific knockdown of ARS2 or MAGL significantly suppressed self-renewal and tumor growth, and increased survival in a mouse intracranial xenograft model of GSCs. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. The M2-like signature is enriched in mesenchymal subtype and predicted poor survival in GBM patients. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.
2020-05-16 | GSE150630 | GEO
Project description:The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. Specific knockdown of ARS2 or MAGL significantly suppressed self-renewal and tumor growth, and increased survival in a mouse intracranial xenograft model of GSCs. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. The M2-like signature is enriched in mesenchymal subtype and predicted poor survival in GBM patients. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients. Methods: X01 subcutatneous model treated vehicle or JZL184 Results: abstract copy and paste Conclusion: abstract copy and paste
2020-05-16 | GSE150631 | GEO
Project description:ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages I
| PRJNA633041 | ENA
Project description:ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages II
| PRJNA633042 | ENA
Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.
2021-10-01 | GSE140235 | GEO
Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.
2021-10-16 | GSE154346 | GEO
Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.
2021-10-16 | GSE154345 | GEO
Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.
2021-10-16 | GSE154343 | GEO
Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.
2021-10-16 | GSE154342 | GEO
Project description:Glioblastoma (GBM) is the most lethal primary intracranial malignancy, characterized by aggressive recurrence and a dismal prognosis. Despite the implementation of multimodal standard-of-care therapies, including maximal surgical resection, radiotherapy, and chemotherapy, clinical outcomes remain unsatisfactory. A critical determinant of therapeutic resistance is the highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), which constitute 30-50% of the tumor mass, are the predominant immune population within the TME and key orchestrators of GBM-associated immunosuppression. While TAMs predominantly acquire a protumoral M2-like phenotype to facilitate tumor progression via the secretion of cytokines, angiogenic factors, and matrix metalloproteinases, the molecular mechanisms governing this polarization remain elusive. Herein, we identify the immunoregulatory receptor CD300A as a critical driver of M2 macrophage polarization in GBM. Analysis of clinical specimens demonstrated that CD300A is significantly upregulated in GBM tissues and positively correlates with the M2 marker CD163. In a macrophage model, we found that upon M2 induction, CD300A expression was markedly upregulated, paralleling the induction of canonical M2 markers, including CD206 and Arg-1. Functionally, ectopic overexpression of CD300A markedly upregulated canonical M2 markers CD206, Arg-1, and FIZZ1, whereas CD300A knockdown attenuated this phenotype. Mechanistically, we demonstrate that CD300A promotes M2 polarization by activating the JAK2/STAT3 signaling axis. Furthermore, CD300A-mediated M2 polarization was found to enhance the proliferation, migration, and invasion of GBM cells via the induction of VEGFA secretion. Collectively, our findings delineate a novel CD300A-JAK2/STAT3-VEGFA signaling axis that couples immune modulation with malignant progression, highlighting CD300A as a potential therapeutic target for modulating TAMs in GBM.
2026-07-08 | GSE337492 | GEO