A Cell-Surface Membrane Protein Signature for Glioblastoma.
A Cell-Surface Membrane Protein Signature for Glioblastoma.
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DOI：
10.1016/j.cels.2017.03.004
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发表时间：
2017-05-24
期刊：
影响因子：
9.3
通讯作者：
Hood L
中科院分区：
文献类型：
--
作者：
Ghosh D;Funk CC;Caballero J;Shah N;Rouleau K;Earls JC;Soroceanu L;Foltz G;Cobbs CS;Price ND;Hood L
我们提出了一种系统策略，促进胶质母细胞瘤 (GBM) 分子特征的开发，该分子特征由 33 种细胞表面跨膜蛋白组成。这种分子特征 GBMSig 是通过整合 REMBRANDT (n=228) 和 TCGA 数据集 (n=547) 中患者肿瘤的细胞表面蛋白质组学和转录组学开发的，可以在锁定测试中将 GBM 患者与 MCC 值为 0.87 的对照区分开。在功能上，17/33 GBMSig 蛋白与 TGFβ 信号通路相关，包括：CD47、SLC16A1、HMOX1 和 MRC2。这些基因的敲低会损害 GBM 侵袭，反映了它们在 GBM 疾病扰动变化中的作用。对来自多个临床中心的 84 份血浆样本的 GBMSig 子集（CD44、VCAM1、HMOX1 和 BIGH3）进行 ELISA 检测，结果显示 GBM 患者与健康对照之间存在高度分离（ROC 中的 AUC 0.98）。此外，基于这四种蛋白质的分类器区分了肿瘤切除前和肿瘤切除后的血液，证明了作为生物标志物的潜在临床价值。 GBM 细胞表面蛋白的多维分析揭示了可以从 GBM 患者的血液中识别出的破坏的膜信号网络，其中的一个子集可以区分正常个体和患病个体。
We present a systems strategy that facilitated the development of a molecular signature for glioblastoma (GBM), composed of 33 cell-surface transmembrane proteins. This molecular signature, GBMSig was developed through the integration of cell-surface proteomics and transcriptomics from patient tumors in the REMBRANDT (n=228) and TCGA datasets (n=547) and can separate GBM patients from controls with an MCC value of 0.87 in a lock-down-test. Functionally, 17/33 GBMSig proteins are associated with TGFβ signaling pathways, including: CD47, SLC16A1, HMOX1 and MRC2. Knockdown of these genes impaired GBM invasion, reflecting their role in disease-perturbed changes in GBM. ELISA assays for a subset of GBMSig (CD44, VCAM1, HMOX1, and BIGH3) on 84 plasma specimens from multiple clinical sites revealed a high degree of separation of GBM patients from healthy controls (AUC 0.98 in ROC). Additionally, a classifier based on these four proteins differentiated the blood of pre- and post-tumor resections, demonstrating potential clinical value as biomarkers. Multidimensional analysis of GBM cell-surface proteins reveals a disrupted membrane-signaling network that can be identified from the blood of GBM patients, a subset of which can distinguish between normal and diseased individuals.
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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