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; Jong Bae Park

doi:10.1038/s41467-020-16789-2

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 GwakHeon Yoo, Antonio Iavarone, Jong Heon Kim, Jong Bae Park

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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.

Original language	English
Article number	2978
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16789-2
Publication status	Published - 2020 Dec 1

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Yin, J., Kim, S. S., Choi, E., Oh, Y. T., Lin, W., Kim, T. H., Sa, J. K., Hong, J. H., Park, S. H., Kwon, H. J., Jin, X., You, Y., Kim, J. H., Kim, H., Son, J., Lee, J., Nam, D. H., Choi, K. S., Shi, B., ... Park, J. B. (2020). ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages. Nature communications, 11(1), Article 2978. https://doi.org/10.1038/s41467-020-16789-2

Yin, J, Kim, SS, Choi, E, Oh, YT, Lin, W, Kim, TH, Sa, JK, Hong, JH, Park, SH, Kwon, HJ, Jin, X, You, Y, Kim, JH, Kim, H, Son, J, Lee, J, Nam, DH, Choi, KS, Shi, B, Gwak, HS, Yoo, H, Iavarone, A, Kim, JH & Park, JB 2020, 'ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages', Nature communications, vol. 11, no. 1, 2978. https://doi.org/10.1038/s41467-020-16789-2

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

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.",

author = "Jinlong Yin and Kim, {Sung Soo} and Eunji Choi and Oh, {Young Taek} and Weiwei Lin and Kim, {Tae Hoon} and Sa, {Jason K.} and Hong, {Jun Hee} and Park, {Se Hwan} and Kwon, {Hyung Joon} and Xiong Jin and Yeonhee You and Kim, {Ji Hye} and Hyunggee Kim and Jaekyoung Son and Jeongwu Lee and Nam, {Do Hyun} and Choi, {Kui Son} and Bingyang Shi and Gwak, {Ho Shin} and Heon Yoo and Antonio Iavarone and Kim, {Jong Heon} and Park, {Jong Bae}",

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AU - Oh, Young Taek

AU - Lin, Weiwei

AU - Kim, Tae Hoon

AU - Sa, Jason K.

AU - Hong, Jun Hee

AU - Park, Se Hwan

AU - Kwon, Hyung Joon

AU - Jin, Xiong

AU - You, Yeonhee

AU - Kim, Ji Hye

AU - Kim, Hyunggee

AU - Son, Jaekyoung

AU - Lee, Jeongwu

AU - Nam, Do Hyun

AU - Choi, Kui Son

AU - Shi, Bingyang

AU - Gwak, Ho Shin

AU - Yoo, Heon

AU - Iavarone, Antonio

AU - Kim, Jong Heon

AU - Park, Jong Bae

PY - 2020/12/1

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N2 - 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.

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

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