GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

Marta Moreno; Leire Pedrosa; Laia Pare; Estela Pineda; Leire Bejarano; Josefina Martinez; 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 Gomez-Manzano; Francesc Graus; Erik P. Sulman; Xianhua Piao; Ichiro Nakano; Aleix Prat; Krishna P. Bhat; Nuria 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 Pare, Estela Pineda, Leire Bejarano, Josefina Martinez, 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 Gomez-Manzano, Francesc Graus, Erik P. Sulman, Xianhua Piao, Ichiro Nakano, Aleix Prat, Krishna P. Bhat, Nuria de la Iglesia^*

^*Corresponding author for this work

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

29 Citations (Scopus)

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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 classicalGBMs 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-kappa B) 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
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
Publication status	Published - 21-Nov-2017

Keywords

PROTEIN-COUPLED RECEPTOR
INTEGRATED GENOMIC ANALYSIS
NF-KAPPA-B
BREAST-CANCER
RADIATION RESPONSE
GENE-EXPRESSION
STEM-CELLS
MALIGNANT GLIOMA
GROWTH-FACTOR
RNA-SEQ

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GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in GlioblastomaFinal publisher's version, 625 KBLicence: CC BY-NC-ND

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Moreno, M., Pedrosa, L., Pare, L., Pineda, E., Bejarano, L., Martinez, 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, Marta ; Pedrosa, Leire ; Pare, Laia ; Pineda, Estela ; Bejarano, Leire ; Martinez, Josefina ; Balasubramaniyan, Veerakumar ; Ezhilarasan, Ravesanker ; Kallarackal, Naveen ; Kim, Sung-Hak ; Wang, Jia ; Audia, Alessandra ; Conroy, Siobhan ; Marin, Mercedes ; Ribalta, Teresa ; Pujol, Teresa ; Herreros, Antoni ; Tortosa, Avelina ; Mira, Helena ; Alonso, Marta M. ; Gomez-Manzano, Candelaria ; Graus, Francesc ; Sulman, Erik P. ; Piao, Xianhua ; Nakano, Ichiro ; Prat, Aleix ; Bhat, Krishna P. ; de la Iglesia, Nuria. / GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma. In: Cell reports. 2017 ; Vol. 21, No. 8. pp. 2183-2197.

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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 classicalGBMs 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-kappa B) 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.",

keywords = "PROTEIN-COUPLED RECEPTOR, INTEGRATED GENOMIC ANALYSIS, NF-KAPPA-B, BREAST-CANCER, RADIATION RESPONSE, GENE-EXPRESSION, STEM-CELLS, MALIGNANT GLIOMA, GROWTH-FACTOR, RNA-SEQ",

author = "Marta Moreno and Leire Pedrosa and Laia Pare and Estela Pineda and Leire Bejarano and Josefina Martinez 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 Gomez-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}, Nuria",

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Moreno, M, Pedrosa, L, Pare, L, Pineda, E, Bejarano, L, Martinez, 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, Gomez-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

GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma. / Moreno, Marta; Pedrosa, Leire; Pare, Laia; Pineda, Estela; Bejarano, Leire; Martinez, Josefina; Balasubramaniyan, Veerakumar; Ezhilarasan, Ravesanker; Kallarackal, Naveen; Kim, Sung-Hak; Wang, Jia; Audia, Alessandra; Conroy, Siobhan; Marin, Mercedes; Ribalta, Teresa; Pujol, Teresa; Herreros, Antoni; Tortosa, Avelina; Mira, Helena; Alonso, Marta M.; Gomez-Manzano, Candelaria; Graus, Francesc; Sulman, Erik P.; Piao, Xianhua; Nakano, Ichiro; Prat, Aleix; Bhat, Krishna P.; de la Iglesia, Nuria.

In: Cell reports, Vol. 21, No. 8, 21.11.2017, p. 2183-2197.

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

TY - JOUR

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

AU - Moreno, Marta

AU - Pedrosa, Leire

AU - Pare, Laia

AU - Pineda, Estela

AU - Bejarano, Leire

AU - Martinez, 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 - Gomez-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, Nuria

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 classicalGBMs 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-kappa B) 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 classicalGBMs 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-kappa B) 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.

KW - PROTEIN-COUPLED RECEPTOR

KW - INTEGRATED GENOMIC ANALYSIS

KW - NF-KAPPA-B

KW - BREAST-CANCER

KW - RADIATION RESPONSE

KW - GENE-EXPRESSION

KW - STEM-CELLS

KW - MALIGNANT GLIOMA

KW - GROWTH-FACTOR

KW - RNA-SEQ

U2 - 10.1016/j.celrep.2017.10.083

DO - 10.1016/j.celrep.2017.10.083

M3 - Article

C2 - 29166609

VL - 21

SP - 2183

EP - 2197

JO - Cell reports

JF - Cell reports

SN - 2211-1247

IS - 8

ER -