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Effect of TAM_MK-8931 treatment on TAMs gene expression

ABSTRACT: Glioblastoma (GBM), contains different tumor-associated macrophage (TAM) populations that can either promote tumor growth and therapeutic resistance (pTAMs) or have tumor suppressive properties (sTAMs), and thus reprograming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small molecule compounds we find that inhibition of the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) by TAM_MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with TAM_MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required for maintaining pTAM polarization through trans-IL-6-sIL-6R-STAT3 signaling. TAM_MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease in clinical trials, and have been shown to be safe for humans, these could be potentially streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy in GBM.

ORGANISM(S): Mus musculus

PROVIDER: GSE181650 | GEO | 2021/08/26

REPOSITORIES: GEO

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Effect of MK-8931 on GSC gene expression

Project description:Glioblastoma (GBM), contains different tumor-associated macrophage (TAM) populations that can either promote tumor growth and therapeutic resistance (pTAMs) or have tumor suppressive properties (sTAMs), and thus reprograming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small molecule compounds we find that inhibition of the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) by MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required for maintaining pTAM polarization through trans-IL-6-sIL-6R-STAT3 signaling. MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease in clinical trials, and have been shown to be safe for humans, these could be potentially streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy in GBM.

2021-08-26 | GSE181649 | GEO

Increased IL-6 Trans-Signaling in the Airways After an Allergen Challenge

Project description:The pro-inflammatory cytokine IL-6 is elevated in both blood and airways in asthma. IL-6 signaling is regulated by its receptor composed of two proteins, IL-6R and GP130, that are found in both membrane and soluble forms. The interaction of IL-6 with soluble IL-6R (sIL-6R) can trigger IL-6 trans-signaling in cells such as epithelial cells and fibroblasts, which express GP130, but do not produce sufficient IL-6R. We aimed to analyze IL-6 trans-signaling in the airways after an allergen challenge and to examine the potential source of sIL-6R and sGP130. In addition to protein analysis of bronchoalveolar lavages by ELISA and flow cytometry, we performed next-generation RNA sequencing (RNA-seq) to study the expression of the IL-6R subunits by eosinophils activated by IL-3 in vitro. RNA-seq and proteomic analyses confirmed that eosinophils do not produce GP130 but produce both IL-6R and ADAM10, a metalloproteinase that cleaves membrane IL-6R into sIL-6R.

2020-10-22 | GSE159782 | GEO

An engineered glioblastoma model yields macrophage-secreted drivers of invasion

Project description:Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFβI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.

2023-12-21 | GSE251777 | GEO

Microglia promote glioblastoma growth via mTOR-mediated immunosuppressive conditioning of the tumor microenvironment.

Project description:Tumor-associated microglia and macrophages (TAM) are the most numerous non-neoplastic populations in the tumor microenvironment of glioblastoma (GBM), the most common malignant brain tumor in adulthood. The mTOR pathway, an important regulator of cell survival and proliferation, is known to be upregulated in GBM, but little is known about a potential role of this pathway in TAM. Here, we show that GBM-initiating cells (GIC) induce mTOR signalling in TAM-Microglia (TAM-MG) but not TAM-Macrophages (TAM-BMDM) in in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-ĸB activity promotes an immunosuppressed phenotype in TAM-MG which hinders effector T cell proliferation and immune reactivity, thereby contributing to tumor immune evasion and promoting tumor growth in a mouse model. The translational value of these results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model whereby IPSC-derived microglia-like cells are conditioned by syngeneic patient-derived GIC. These results raise the possibility that tumor cells might not be the primary target of mTOR inhibition, and TAM-MG should be considered instead.

2020-07-21 | GSE147329 | GEO

Capase-1 cleaves PPARg for potentitating the pro-tumor action of TAMs

Project description:Tumor-associated macrophages (TAMs) are increasingly viewed as a target of great relevance in the tumor microenvironment, because of their important role in cancer progression and metastasis. However, the endogenous regulatory mechanisms underlying TAM differentiation remain largely unknown. Here, we report that caspase-1 promotes TAM differentiation by cleaving peroxisome proliferator-activated receptor gamma (PPARγ) at Asp64, thus generating a 41 kDa fragment. This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation, thereby leading to the accumulation of lipid droplets and promoting TAM differentiation. Furthermore, the administration of caspase-1 inhibitors or the infusion of bone marrow-derived macrophages (BMDMs) genetically engineered to overexpress murine MCAD markedly suppresses tumor growth. Therefore, targeting the caspase-1/PPARγ/MCAD pathway might be a promising therapeutic approach to prevent tumor progression.

2017-06-14 | GSE99960 | GEO

Malignant ascites microenvironment induced macrophage reprogramming facilities epithelial ovarian cancer peritoneal metastasis

Project description:Macrophages form a primary immune cells population in tumor tissues and malignant ascites microenvironment (MAM). They can be activated and polarized into tumor-associated macrophages (TAM) by the embedded environment and promote tumor progression and metastasis However, the molecular mechanisms of MAM in macrophage polarization and the effects on epithelial ovarian cancer (EOC) metastatic progression remain elusive. Here, we found that that MAM modulates RhoA-GTPase-F-actin-Hippo signaling cascade in facilitating M2-like macrophage polarization that, in turn, promotes tumor dissemination. PUFA enriched magligant ascites microenvironment promote macrophage lipid oxidative phosphorylation and supression RhoA-GTPase-Yap1 axis. Genetic ablation Yap1 in macrophage exhibited M2-like polarization and enhanced ovrian tumor dissemination. Pharmacology inhibit Mst1/2 could rescue M2-like TAM polarization in MAM and alter the lipid oxidation of macrophages in MAM, more importantly, inhibit ovarian metastatic properties. Through comparasion primary TAM (P-TAM) and metastasis TAM (M-TAM), we proved that Hippo-Yap1 siganl results M-TAM with high M2/M1 ratio. These findings implicate critical functions of PUFA modulate RhoA-Hippo axis in facility TAM polarization and also suggest manipulation of PUFA metabolism or RhoA-Hippo siganl as a therapeutic strategy aganist EOC metastasis.

2024-05-01 | GSE175552 | GEO

Siglec-9 acts as an immune checkpoint molecule on macrophages in glioblastoma, restricting T cell priming and immunotherapy response [bulk RNA-seq]

Project description:The neoadjuvant immune checkpoint blockade therapy only benefits a limited fraction of glioblastoma multiforme (GBM) patients. Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of GBM patients treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage (TAM) subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the non-responders to anti-PD-1 treatment. Deletion of Siglece (murine homologue) resulted in significantly restrained tumor development and prolonged survival in mouse models. Mechanistically, targeting Siglece directly activated both CD4+ T cells and CD8+ T cells through antigen presentation, secreted chemokines and co-stimulatory factor interactions. Furthermore, Siglece deletion synergized with anti-PD-1/PD-L1 treatment to improve antitumor efficacy. Our data demonstrated that Siglec-9 is an immune checkpoint molecule on macrophages that can be targeted to enhance anti-PD-1/PD-L1 therapeutic efficacy for GBM treatment.

2023-06-29 | GSE235911 | GEO

Siglec-9 acts as an immune checkpoint molecule on macrophages in glioblastoma, restricting T cell priming and immunotherapy response [scRNA-seq]

2023-06-29 | GSE235676 | GEO

Siglec-9 acts as an immune checkpoint molecule on macrophages in glioblastoma, restricting T cell priming and immunotherapy response [ST]

2023-06-29 | GSE235672 | GEO

Transcriptome sequencing analysis of CSF-1Rhigh TAMs and CSF-1Rlow TAMs in colon adenocarcinoma.

Project description:Tumor-associated macrophages (TAMs) are a major component of the leukocyte and a heterogenous population in tumors. Recent reports have increasingly suggested that manipulating the function of TAMs may serve as a promising therapeutic strategy against advanced tumors. Our present work indicates that CSF-1R+ TAMs are abundantly found in a significant proportion of COAD specimens. Therefore，to determine the role of the CSF-1Rhigh TAMs in COAD, we sorted the CSF-1Rhigh TAMs and the CSF-1R low TAMs from the colon adenocarcinomas for Smart-seq2. We found that CSF-1Rhigh TAM infiltration involved in multiple tumor immune signaling pathways. CSF-1Rhigh TAMs mostly exhibited a immunosuppressive phenotypes, and were associated with enhanced levels of Treg cells. CSF-1R high TAMs promotes COAD progression by modulating tumor immunity environment

2022-03-31 | GSE193814 | GEO

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