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

  • Cell Stem Cell. 2022 Oct 12;S1934-5909(22)00417-9. doi: 10.1016/j.stem.2022.09.009.
Jiayi Chen  1 ,  Guangqin Liu  2 ,  Xinzheng Wang  1 ,  Hao Hong  1 ,  Tingting Li  1 ,  Lin Li  1 ,  Hongxiang Wang  3 ,  Jiong Xie  4 ,  Bohan Li  4 ,  Ting Li  1 ,  Dingyi Lu  1 ,  Yakun Zhang  1 ,  Haixin Zhao  5 ,  Chengcheng Yao  1 ,  Kaiqing Wen  1 ,  Teng Li  1 ,  Jing Chen  1 ,  Shengming Wu  1 ,  Kun He  1 ,  Wei-Na Zhang  1 ,  Jie Zhao  1 ,  Na Wang  1 ,  Qiuying Han  1 ,  Qing Xia  1 ,  Ji Qi  4 ,  Juxiang Chen  3 ,  Tao Zhou  1 ,  Jianghong Man  1 ,  Xue-Min Zhang  2 ,  Ai-Ling Li  6 ,  Xin Pan  7
Affiliations
  • 1. Nanhu Laboratory, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
  • 2. Nanhu Laboratory, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 3. Department of Neurosurgery, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China.
  • 4. Fengtai Hospital, 99 Fengtai South Road, Beijing, China.
  • 5. Nanhu Laboratory, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; State Key Laboratory of Experimental Haematology, Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 6. Nanhu Laboratory, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 7. Nanhu Laboratory, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
PMID: 36265493 DOI: 10.1016/j.stem.2022.09.009
Abstract

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.

Keywords
GBM; angiogenesis; epigenetics; glioblastoma stem cells; histamine; histidine decarboxylase; tumor microenvironment.
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