Jinlong Yin^1,2,3,13, Sung Soo Kim^2,3,13, Eunji Choi^4,13, Young Taek Oh^3,5,6,13, Weiwei Lin³,
Tae-Hoon Kim³, Jason K. Sa^5,7, Jun Hee Hong³, Se Hwan Park², Hyung Joon Kwon⁴, Xiong Jin^8,12, Yeonhee You², Ji Hye Kim⁹, Hyunggee Kim⁸, Jaekyoung Son⁹, Jeongwu Lee¹⁰, Do-Hyun Nam⁵, Kui Son Choi⁴, Bingyang Shi¹, Ho-Shin Gwak⁴, Heon Yoo^2,3, Antonio Iavarone^6,*, Jong Heon Kim^2,11,* & Jong Bae Park^2,3,*

¹Henan and Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China.
²Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
³Rare Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
⁴Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
⁵Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
⁶Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA. ⁷Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea. ⁸Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
⁹Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
¹⁰Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
¹¹Division of Cancer Biology, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
¹²Present address: Laboratory of Stem Cells, NEXELCo., Ltd., Seoul, Republic of Korea.

¹³These authors contributed equally: Jinlong Yin, Eunji Choi, Sung Soo Kim, Young Taek Oh.

^*Corresponding author

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.