Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.
Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.
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DOI：
10.1038/s43018-021-00267-9
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发表时间：
2021-11
期刊：
影响因子：
22.7
通讯作者：
Bao S
中科院分区：
文献类型：
--
作者：
Zhai K;Huang Z;Huang Q;Tao W;Fang X;Zhang A;Li X;Stark GR;Hamilton TA;Bao S
胶质母细胞瘤（GBM）含有丰富的肿瘤相关巨噬细胞（TAM）。大多数TAM是促肿瘤巨噬细胞（pTAM），而肿瘤抑制巨噬细胞（sTAM）是少数。因此，将pTAM重编程为sTAM代表了一种有吸引力的治疗策略。通过筛选一系列小分子化合物，我们发现MK-8931抑制β位点淀粉样前体蛋白裂解酶1（BACE 1）可有效地将pTAM重编程为sTAM，并促进胶质瘤细胞的巨噬细胞吞噬作用;此外，低剂量辐射可显著增强TAM浸润，并与MK-8931治疗协同抑制恶性生长。BACE 1优先由人GBM中的pTAM表达，并且是通过trans-IL-6-sIL-6 R-STAT 3信号传导维持pTAM极化所必需的。由于MK-8931和其他BACE 1抑制剂已被开发用于阿尔茨海默病，并且在临床试验中已被证明对人类安全，因此这些抑制剂可能被简化用于癌症治疗。总的来说，这项研究提供了一个有前途的治疗方法，以加强巨噬细胞为基础的治疗恶性肿瘤。
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, reprograming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small molecule compounds, we find that inhibiting 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. 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 be potentially streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy for malignant tumors.
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影响因子：
64.8
作者：
Guerriero JL;Sotayo A;Ponichtera HE;Castrillon JA;Pourzia AL;Schad S;Johnson SF;Carrasco RD;Lazo S;Bronson RT;Davis SP;Lobera M;Nolan MA;Letai A
通讯作者：
Letai A
DOI：
10.1073/pnas.1721434116
发表时间：
2019-01-15
影响因子：
11.1
作者：
Hutter, Gregor;Theruvath, Johanna;Cheshier, Samuel H.
通讯作者：
Cheshier, Samuel H.
影响因子：
46.9
作者：
Klichinsky M;Ruella M;Shestova O;Lu XM;Best A;Zeeman M;Schmierer M;Gabrusiewicz K;Anderson NR;Petty NE;Cummins KD;Shen F;Shan X;Veliz K;Blouch K;Yashiro-Ohtani Y;Kenderian SS;Kim MY;O'Connor RS;Wallace SR;Kozlowski MS;Marchione DM;Shestov M;Garcia BA;June CH;Gill S
通讯作者：
Gill S
DOI：
10.1056/nejmoa1706441
发表时间：
2018-05-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Egan MF;Kost J;Tariot PN;Aisen PS;Cummings JL;Vellas B;Sur C;Mukai Y;Voss T;Furtek C;Mahoney E;Harper Mozley L;Vandenberghe R;Mo Y;Michelson D
通讯作者：
Michelson D
影响因子：
13.6
作者：
Guerriero JL
通讯作者：
Guerriero JL