GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

Marta Moreno; Leire Pedrosa; Laia Paré; Estela Pineda; Leire Bejarano; Josefina Martínez; Veerakumar Balasubramaniyan; Ravesanker Ezhilarasan; Naveen Kallarackal; Sung-Hak Kim; Jia Wang; Alessandra Audia; Siobhan Conroy; Mercedes Marin; Teresa Ribalta; Teresa Pujol; Antoni Herreros; Avelina Tortosa; Helena Mira; Marta M Alonso; Candelaria Gómez-Manzano; Francesc Graus; Erik P Sulman; Xianhua Piao; Ichiro Nakano; Aleix Prat; Krishna P Bhat; Núria de la Iglesia

doi:10.1016/j.celrep.2017.10.083

GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

Marta Moreno, Leire Pedrosa, Laia Paré, Estela Pineda, Leire Bejarano, Josefina Martínez, Veerakumar Balasubramaniyan, Ravesanker Ezhilarasan, Naveen Kallarackal, Sung-Hak Kim, Jia Wang, Alessandra Audia, Siobhan Conroy, Mercedes Marin, Teresa Ribalta, Teresa Pujol, Antoni Herreros, Avelina Tortosa, Helena Mira, Marta M AlonsoCandelaria Gómez-Manzano, Francesc Graus, Erik P Sulman, Xianhua Piao, Ichiro Nakano, Aleix Prat, Krishna P Bhat, Núria de la Iglesia

Neuro-Oncology

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

Abstract

A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM.

Original language	English (US)
Pages (from-to)	2183-2197
Number of pages	15
Journal	Cell Reports
Volume	21
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2017.10.083
State	Published - Nov 21 2017

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Moreno, M., Pedrosa, L., Paré, L., Pineda, E., Bejarano, L., Martínez, J., Balasubramaniyan, V., Ezhilarasan, R., Kallarackal, N., Kim, S.-H., Wang, J., Audia, A., Conroy, S., Marin, M., Ribalta, T., Pujol, T., Herreros, A., Tortosa, A., Mira, H., ... de la Iglesia, N. (2017). GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma. Cell Reports, 21(8), 2183-2197. https://doi.org/10.1016/j.celrep.2017.10.083

Moreno, M, Pedrosa, L, Paré, L, Pineda, E, Bejarano, L, Martínez, J, Balasubramaniyan, V, Ezhilarasan, R, Kallarackal, N, Kim, S-H, Wang, J, Audia, A, Conroy, S, Marin, M, Ribalta, T, Pujol, T, Herreros, A, Tortosa, A, Mira, H, Alonso, MM, Gómez-Manzano, C, Graus, F, Sulman, EP, Piao, X, Nakano, I, Prat, A, Bhat, KP & de la Iglesia, N 2017, 'GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma', Cell Reports, vol. 21, no. 8, pp. 2183-2197. https://doi.org/10.1016/j.celrep.2017.10.083

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title = "GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma",

abstract = "A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM.",

author = "Marta Moreno and Leire Pedrosa and Laia Par{\'e} and Estela Pineda and Leire Bejarano and Josefina Mart{\'i}nez and Veerakumar Balasubramaniyan and Ravesanker Ezhilarasan and Naveen Kallarackal and Sung-Hak Kim and Jia Wang and Alessandra Audia and Siobhan Conroy and Mercedes Marin and Teresa Ribalta and Teresa Pujol and Antoni Herreros and Avelina Tortosa and Helena Mira and Alonso, {Marta M} and Candelaria G{\'o}mez-Manzano and Francesc Graus and Sulman, {Erik P} and Xianhua Piao and Ichiro Nakano and Aleix Prat and Bhat, {Krishna P} and {de la Iglesia}, N{\'u}ria",

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doi = "10.1016/j.celrep.2017.10.083",

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T1 - GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

AU - Moreno, Marta

AU - Pedrosa, Leire

AU - Paré, Laia

AU - Pineda, Estela

AU - Bejarano, Leire

AU - Martínez, Josefina

AU - Balasubramaniyan, Veerakumar

AU - Ezhilarasan, Ravesanker

AU - Kallarackal, Naveen

AU - Kim, Sung-Hak

AU - Wang, Jia

AU - Audia, Alessandra

AU - Conroy, Siobhan

AU - Marin, Mercedes

AU - Ribalta, Teresa

AU - Pujol, Teresa

AU - Herreros, Antoni

AU - Tortosa, Avelina

AU - Mira, Helena

AU - Alonso, Marta M

AU - Gómez-Manzano, Candelaria

AU - Graus, Francesc

AU - Sulman, Erik P

AU - Piao, Xianhua

AU - Nakano, Ichiro

AU - Prat, Aleix

AU - Bhat, Krishna P

AU - de la Iglesia, Núria

PY - 2017/11/21

Y1 - 2017/11/21

N2 - A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM.

AB - A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM.

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DO - 10.1016/j.celrep.2017.10.083

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SN - 2211-1247

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SP - 2183

EP - 2197

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

Abstract

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