Glioblastoma stem cell-specific histamine secretion drives pro-angiogenic tumor microenvironment remodeling

The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understo...

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Published in:Cell stem cell 2022-11, Vol.29 (11), p.1531-1546.e7
Main Authors: Chen, Jiayi, Liu, Guangqin, Wang, Xinzheng, Hong, Hao, Li, Tingting, Li, Lin, Wang, Hongxiang, Xie, Jiong, Li, Bohan, Li, Ting, Lu, Dingyi, Zhang, Yakun, Zhao, Haixin, Yao, Chengcheng, Wen, Kaiqing, Li, Teng, Chen, Jing, Wu, Shengming, He, Kun, Zhang, Wei-Na, Zhao, Jie, Wang, Na, Han, Qiuying, Xia, Qing, Qi, Ji, Chen, Juxiang, Zhou, Tao, Man, Jianghong, Zhang, Xue-Min, Li, Ai-Ling, Pan, Xin
Format: Article
Language:English
Subjects:
angiogenesis
Animals
Brain Neoplasms - pathology
Cell Line, Tumor
Endothelial Cells - metabolism
epigenetics
GBM
Glioblastoma - pathology
glioblastoma stem cells
histamine
Histamine - metabolism
histidine decarboxylase
Humans
Mice
Neoplastic Stem Cells - pathology
Tumor Microenvironment
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Summary:The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understood. In this study, we interrogated metabolites that are preferentially secreted from GSCs and found that GSCs produce and secrete histamine to shape a pro-angiogenic tumor microenvironment. This histamine-producing ability is attributed to H3K4me3 modification-activated histidine decarboxylase (HDC) transcription via MYC. Notably, HDC is highly expressed in GBM, which is associated with poor survival of these patients. GSC-secreted histamine activates endothelial cells by triggering a histamine H1 receptor (H1R)-Ca2+-NF-κB axis, thereby promoting angiogenesis and GBM progression. Importantly, pharmacological blockage of H1R using antihistamines impedes the growth of GBM xenografts in mice. Our findings establish that GSC-specific metabolite secretion remodels the tumor microenvironment and highlight histamine targeting as a potential strategy for GBM therapy. [Display omitted] •Histamine synthesis and secretion are enhanced in GSCs•Epigenetic activation of HDC drives GSC to secrete histamine•GSC-secreted histamine promotes glioblastoma progression by increasing angiogenesis•Pharmacological inhibition of GSC-secreted histamine impedes GBM progression Brain tumors, particularly GBM, exhibit extremely high angiogenesis and vascularity. Chen et al. demonstrate that GSCs secrete histamine to hijack endothelial cells and promote angiogenesis for GBM progression. Pharmacological blockage of this brain-resident histamine with antihistamines inhibits GBM angiogenesis and prolongs the survival of GBM-bearing mice.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2022.09.009