Identification of growth hormone receptor as a relevant target for precision medicine in low-EGFR expressing glioblastoma.
Identification of growth hormone receptor as a relevant target for precision medicine in low-EGFR expressing glioblastoma.
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DOI：
10.1002/ctm2.939
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发表时间：
2022-07
影响因子：
10.6
通讯作者：
Idbaih, Ahmed
中科院分区：
文献类型：
--
作者：
Verreault, Maite;Segoviano Vilchis, Irma;Rosenberg, Shai;Lemaire, Nolwenn;Schmitt, Charlotte;Guehennec, Jeremy;Royer-Perron, Louis;Thomas, Jean-Leon;Lam, TuKiet T.;Dingli, Florent;Loew, Damarys;Ducray, Francois;Paris, Sophie;Carpentier, Catherine;Marie, Yannick;Laigle-Donadey, Florence;Rousseau, Audrey;Pigat, Natascha;Boutillon, Florence;Bielle, Franck;Mokhtari, Karima;Frank, Stuart J.;de Reynies, Aurelien;Hoang-Xuan, Khe;Sanson, Marc;Goffin, Vincent;Idbaih, Ahmed
关键词：
需要新的治疗方法来改善胶质母细胞瘤（GBM）患者的预后。为了确定异常激活的表皮生长因子受体（EGFR）信号传导的替代致癌机制，这是GBM中最常见的致癌机制之一，我们对一系列54例人类GBM样本的基因表达谱进行了比较分析。然后，我们在GBM患者来源的细胞系中进行了功能增益以及遗传和药理学抑制试验，以从功能上验证我们的发现。我们发现生长激素受体（GHR）信号传导定义了缺乏EGFR过表达的GBMs的一个独特的分子亚群。在三分之一的患者中检测到GHR过表达，并且由于SOCS2启动子超甲基化，GHR过表达与细胞因子信号传导2 （SOCS2）抑制因子表达水平低有关。在GBM患者来源的细胞系中，GHR信号调节参与细胞运动的蛋白质的表达，促进细胞在体外的迁移、侵袭和增殖，并促进体内肿瘤的发生、肿瘤生长和肿瘤侵袭。GHR基因和药理学抑制可降低体外细胞增殖和迁移。本研究为改善GBM患者预后开辟了新的研究领域。在三分之一的GBM患者中观察到GHR过表达。GHR过表达与SOCS2启动子超甲基化相关，导致SOCS2表达水平低。GHR信号在体外促进细胞迁移、侵袭和增殖，在体内促进肿瘤发生、肿瘤生长和肿瘤侵袭。基因和药理学抑制GHR可减少体外细胞增殖和迁移。
New therapeutic approaches are needed to improve the prognosis of glioblastoma (GBM) patients. With the objective of identifying alternative oncogenic mechanisms to abnormally activated epidermal growth factor receptor (EGFR) signalling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We then conducted gain of function as well as genetic and pharmocological inhibition assays in GBM patient‐derived cell lines to functionnally validate our finding. We identified that growth hormone receptor (GHR) signalling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of suppressor of cytokine signalling 2 (SOCS2) expression due to SOCS2 promoter hypermethylation. In GBM patient‐derived cell lines, GHR signalling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro and promotes tumourigenesis, tumour growth, and tumour invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro. This study pioneers a new field of investigation to improve the prognosis of GBM patients. GHR overexpression is observed in one third of GBM patients. GHR overexpression is associated with SOCS2 promoter hypermethylation leading to low levels of SOCS2 expression. GHR signalling promotes cell migration, invasion and proliferation in vitro and promotes tumourigenesis, tumour growth and tumour invasiveness in vivo. Genetic and pharmacological GHR inhibition reduces cell proliferation and migration in vitro.
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影响因子：
--
作者：
Basu R;Wu S;Kopchick JJ
通讯作者：
Kopchick JJ
影响因子：
4.1
作者：
Davey, HW;McLachlan, MJ;Adams, TE
通讯作者：
Adams, TE
影响因子：
5.2
作者：
Dehkhoda F;Lee CMM;Medina J;Brooks AJ
通讯作者：
Brooks AJ
影响因子：
4.8
作者：
He, K;Loesch, K;Frank, SJ
通讯作者：
Frank, SJ
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth