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Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.

ABSTRACT: Glioblastoma (GBM) contains abundant tumor-associated macrophages (TAMs). The majority of TAMs are tumor-promoting macrophages (pTAMs), while tumor-suppressive macrophages (sTAMs) are the minority. Thus, reprogramming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small-molecule compounds, we find that inhibiting β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with 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 to maintain pTAM polarization through trans-interleukin 6 (IL-6)-soluble IL-6 receptor (sIL-6R)-signal transducer and activator of transcription 3 (STAT3) signaling. Because MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease and have been shown to be safe for humans in clinical trials, these inhibitors could potentially be streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy for malignant tumors.

SUBMITTER: Zhai K

PROVIDER: S-EPMC8809483 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.

Zhai Kui K Huang Zhi Z Huang Qian Q Tao Weiwei W Fang Xiaoguang X Zhang Aili A Li Xiaoxia X Stark George R GR Hamilton Thomas A TA Bao Shideng S

Nature cancer 20211108 11

Glioblastoma (GBM) contains abundant tumor-associated macrophages (TAMs). The majority of TAMs are tumor-promoting macrophages (pTAMs), while tumor-suppressive macrophages (sTAMs) are the minority. Thus, reprogramming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small-molecule compounds, we find that inhibiting β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagoc ...[more]

PMID: 35122055

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Project description:RationaleTGF (transforming growth factor)-β is critically involved in myocardial injury, repair, and fibrosis, activating both Smad (small mothers against decapentaplegic)-dependent and non-Smad pathways. The in vivo role of TGF-β signaling in regulation of macrophage function is poorly understood. We hypothesized that in the infarcted myocardium, activation of TGF-β/Smad signaling in macrophages may regulate repair and remodeling.ObjectiveTo investigate the role of macrophage-specific TGF-β Smad3 signaling in a mouse model of myocardial infarction and to dissect the mechanisms mediating Smad-dependent modulation of macrophage function.Methods and resultsTGF-βs markedly activated Smad3 in macrophages, without affecting Smad-independent pathways. Phagocytosis rapidly and directly activated macrophage Smad3, in the absence of active TGF-β release. MyS3KO (myeloid cell-specific Smad3 knockout) mice had no baseline defects but exhibited increased late mortality and accentuated dilative postmyocardial infarction remodeling. Adverse outcome in infarcted MyS3KO mice was associated with perturbations in phagocytic activity, defective transition of macrophages to an anti-inflammatory phenotype, scar expansion, and accentuated apoptosis of border zone cardiomyocytes. In vitro, Smad3 null macrophages exhibited reduced expression of genes associated with eat-me signals, such as Mfge8 (milk fat globule-epidermal growth factor factor 8), and reduced capacity to produce the anti-inflammatory mediators IL (interleukin)-10 and TGF-β1, and the angiogenic growth factor VEGF (vascular endothelial growth factor). Mfge8 partly rescued the phagocytic defect of Smad3 null macrophages, without affecting inflammatory activity. Impaired anti-inflammatory actions of Smad3 null macrophages were associated with marked attenuation of phagocytosis-induced PPAR (peroxisome proliferator-activated receptor) expression. MyS3KO mice had no significant alterations in microvascular density and interstitial fibrosis in remodeling myocardial segments.ConclusionsWe demonstrate that Smad3 critically regulates function of infarct macrophages, by mediating acquisition of a phagocytic phenotype and by contributing to anti-inflammatory transition. Smad3-dependent actions in macrophages protect the infarcted heart from adverse remodeling.

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Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.

Publications

Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.

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