ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages

Jinlong Yin (), Sung Soo Kim, Eunji Choi, Young Taek Oh, Weiwei Lin, Tae-Hoon Kim, Jason K. Sa, Jun Hee Hong, Se Hwan Park, Hyung Joon Kwon, Xiong Jin, Yeonhee You, Ji Hye Kim, Hyunggee Kim, Jaekyoung Son, Jeongwu Lee, Do-Hyun Nam, Kui Son Choi, Bingyang Shi, Ho-Shin Gwak, Heon Yoo, Antonio Iavarone (), Jong Heon Kim () and Jong Bae Park ()
Additional contact information
Jinlong Yin: Henan and Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University
Sung Soo Kim: Graduate School of Cancer Science and Policy, National Cancer Center
Eunji Choi: Graduate School of Cancer Science and Policy, National Cancer Center
Young Taek Oh: Rare Cancer Branch, Research Institute and Hospital, National Cancer Center
Weiwei Lin: Rare Cancer Branch, Research Institute and Hospital, National Cancer Center
Tae-Hoon Kim: Rare Cancer Branch, Research Institute and Hospital, National Cancer Center
Jason K. Sa: Sungkyunkwan University
Jun Hee Hong: Rare Cancer Branch, Research Institute and Hospital, National Cancer Center
Se Hwan Park: Graduate School of Cancer Science and Policy, National Cancer Center
Hyung Joon Kwon: Graduate School of Cancer Science and Policy, National Cancer Center
Xiong Jin: Korea University
Yeonhee You: Graduate School of Cancer Science and Policy, National Cancer Center
Ji Hye Kim: University of Ulsan College of Medicine
Hyunggee Kim: Korea University
Jaekyoung Son: University of Ulsan College of Medicine
Jeongwu Lee: Lerner Research Institute, Cleveland Clinic
Do-Hyun Nam: Sungkyunkwan University
Kui Son Choi: Graduate School of Cancer Science and Policy, National Cancer Center
Bingyang Shi: Henan and Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University
Ho-Shin Gwak: Graduate School of Cancer Science and Policy, National Cancer Center
Heon Yoo: Graduate School of Cancer Science and Policy, National Cancer Center
Antonio Iavarone: Columbia University Medical Center
Jong Heon Kim: Graduate School of Cancer Science and Policy, National Cancer Center
Jong Bae Park: Graduate School of Cancer Science and Policy, National Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.

Date: 2020
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DOI: 10.1038/s41467-020-16789-2

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