Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma

Abstract

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.

Keywords

glioma progression / molecular classification / EM/PM subtyping / intratumor heterogeneity

References

[1] Aldape K, Brindle KM, Chesler L, Chopra R, Gajjar A, Gilbert MR, Gottardo N, Gutmann DH, Hargrave D, Holland EC, Jones DTW, Joyce JA, Kearns P, Kieran MW, Mellinghoff IK, Merchant M, Pfister SM, Pollard SM, Ramaswamy V, Rich JN, Robinson GW, Rowitch DH, Sampson JH, Taylor MD, Workman P, Gilbertson RJ. Challenges to curing primary brain tumours. Nat Rev Clin Oncol 2019; 16(8): 509–520

[2] Touat M, Idbaih A, Sanson M, Ligon KL. Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol 2017; 28(7): 1457–1472

[3] Garraway LA, Sellers WR. Lineage dependency and lineage-survival oncogenes in human cancer. Nat Rev Cancer 2006; 6(8): 593–602

[4] Westervelt P, Ley TJ. Seed versus soil: the importance of the target cell for transgenic models of human leukemias. Blood 1999; 93(7): 2143–2148

[5] Alcantara Llaguno SR, Parada LF. Cell of origin of glioma: biological and clinical implications. Br J Cancer 2016; 115(12): 1445–1450

[6] Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131(6): 803–820

[7] Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, Curtis C, Watts C, Tavaré S. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 2013; 110(10): 4009–4014

[8] Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M, Roth P, Rudà R, Short S, Smits M, Taphoorn MJB, von Deimling A, Westphal M, Soffietti R, Reifenberger G, Wick W. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 2021; 18(3): 170–186

[9] Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncol 2021; 23(8): 1231–1251

[10] Cieślik M, Chinnaiyan AM. Cancer transcriptome profiling at the juncture of clinical translation. Nat Rev Genet 2018; 19(2): 93–109

[11] Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN; Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010; 17(1): 98–110

[12] Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, Barthel F, Cho HJ, Lin YH, Satani N, Martinez-Ledesma E, Zheng S, Chang E, Sauvé CG, Olar A, Lan ZD, Finocchiaro G, Phillips JJ, Berger MS, Gabrusiewicz KR, Wang G, Eskilsson E, Hu J, Mikkelsen T, DePinho RA, Muller F, Heimberger AB, Sulman EP, Nam DH, Verhaak RGW. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 2017; 32(1): 42–56.e6

[13] Wang J, Cazzato E, Ladewig E, Frattini V, Rosenbloom DI, Zairis S, Abate F, Liu Z, Elliott O, Shin YJ, Lee JK, Lee IH, Park WY, Eoli M, Blumberg AJ, Lasorella A, Nam DH, Finocchiaro G, Iavarone A, Rabadan R. Clonal evolution of glioblastoma under therapy. Nat Genet 2016; 48(7): 768–776

[14] Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suvà ML, Regev A, Bernstein BE. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014; 344(6190): 1396–1401

[15] Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ, Richman AR, Silverbush D, Shaw ML, Hebert CM, Dewitt J, Gritsch S, Perez EM, Gonzalez Castro LN, Lan X, Druck N, Rodman C, Dionne D, Kaplan A, Bertalan MS, Small J, Pelton K, Becker S, Bonal D, Nguyen QD, Servis RL, Fung JM, Mylvaganam R, Mayr L, Gojo J, Haberler C, Geyeregger R, Czech T, Slavc I, Nahed BV, Curry WT, Carter BS, Wakimoto H, Brastianos PK, Batchelor TT, Stemmer-Rachamimov A, Martinez-Lage M, Frosch MP, Stamenkovic I, Riggi N, Rheinbay E, Monje M, Rozenblatt-Rosen O, Cahill DP, Patel AP, Hunter T, Verma IM, Ligon KL, Louis DN, Regev A, Bernstein BE, Tirosh I, Suvà ML. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 2019; 178(4): 835–849.e21

[16] Kim TM, Huang W, Park R, Park PJ, Johnson MD. A developmental taxonomy of glioblastoma defined and maintained by microRNAs. Cancer Res 2011; 71(9): 3387–3399

[17] Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K; Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010; 17(5): 510–522

[18] Sun Y, Zhang W, Chen D, Lv Y, Zheng J, Lilljebjörn H, Ran L, Bao Z, Soneson C, Sjögren HO, Salford LG, Ji J, French PJ, Fioretos T, Jiang T, Fan X. A glioma classification scheme based on coexpression modules of EGFR and PDGFRA. Proc Natl Acad Sci USA 2014; 111(9): 3538–3543

[19] Li J, Xue Y, Wenger A, Sun Y, Wang Z, Zhang C, Zhang Y, Fekete B, Rydenhag B, Jakola AS, Jiang T, Carén H, Fan X. Individual assignment of adult diffuse gliomas into the EM/PM molecular subtypes using a TaqMan low-density array. Clin Cancer Res 2019; 25(23): 7068–7077

[20] Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006; 9(3): 157–173

[21] Kwon SM, Kang SH, Park CK, Jung S, Park ES, Lee JS, Kim SH, Woo HG. Recurrent glioblastomas reveal molecular subtypes associated with mechanistic implications of drug-resistance. PLoS One 2015; 10(10): e0140528

[22] Joo KM, Kim J, Jin J, Kim M, Seol HJ, Muradov J, Yang H, Choi YL, Park WY, Kong DS, Lee JI, Ko YH, Woo HG, Lee J, Kim S, Nam DH. Patient-specific orthotopic glioblastoma xenograft models recapitulate the histopathology and biology of human glioblastomas in situ. Cell Rep 2013; 3(1): 260–273

[23] Kim J, Lee IH, Cho HJ, Park CK, Jung YS, Kim Y, Nam SH, Kim BS, Johnson MD, Kong DS, Seol HJ, Lee JI, Joo KM, Yoon Y, Park WY, Lee J, Park PJ, Nam DH. Spatiotemporal evolution of the primary glioblastoma genome. Cancer Cell 2015; 28(3): 318–328

[24] Puchalski RB, Shah N, Miller J, Dalley R, Nomura SR, Yoon JG, Smith KA, Lankerovich M, Bertagnolli D, Bickley K, Boe AF, Brouner K, Butler S, Caldejon S, Chapin M, Datta S, Dee N, Desta T, Dolbeare T, Dotson N, Ebbert A, Feng D, Feng X, Fisher M, Gee G, Goldy J, Gourley L, Gregor BW, Gu G, Hejazinia N, Hohmann J, Hothi P, Howard R, Joines K, Kriedberg A, Kuan L, Lau C, Lee F, Lee H, Lemon T, Long F, Mastan N, Mott E, Murthy C, Ngo K, Olson E, Reding M, Riley Z, Rosen D, Sandman D, Shapovalova N, Slaughterbeck CR, Sodt A, Stockdale G, Szafer A, Wakeman W, Wohnoutka PE, White SJ, Marsh D, Rostomily RC, Ng L, Dang C, Jones A, Keogh B, Gittleman HR, Barnholtz-Sloan JS, Cimino PJ, Uppin MS, Keene CD, Farrokhi FR, Lathia JD, Berens ME, Iavarone A, Bernard A, Lein E, Phillips JW, Rostad SW, Cobbs C, Hawrylycz MJ, Foltz GD. An anatomic transcriptional atlas of human glioblastoma. Science 2018; 360(6389): 660–663

[25] Mizrak D, Levitin HM, Delgado AC, Crotet V, Yuan J, Chaker Z, Silva-Vargas V, Sims PA, Doetsch F. Single-cell analysis of regional differences in adult V-SVZ neural stem cell lineages. Cell Rep 2019; 26(2): 394–406.e5

[26] Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, Neftel C, Desai N, Nyman J, Izar B, Luo CC, Francis JM, Patel AA, Onozato ML, Riggi N, Livak KJ, Gennert D, Satija R, Nahed BV, Curry WT, Martuza RL, Mylvaganam R, Iafrate AJ, Frosch MP, Golub TR, Rivera MN, Getz G, Rozenblatt-Rosen O, Cahill DP, Monje M, Bernstein BE, Louis DN, Regev A, Suvà ML. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 2016; 539(7628): 309–313

[27] Darmanis S, Sloan SA, Croote D, Mignardi M, Chernikova S, Samghababi P, Zhang Y, Neff N, Kowarsky M, Caneda C, Li G, Chang SD, Connolly ID, Li Y, Barres BA, Gephart MH, Quake SR. Single-cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep 2017; 21(5): 1399–1410

[28] Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, Hovestadt V, Escalante LE, Shaw ML, Rodman C, Gillespie SM, Dionne D, Luo CC, Ravichandran H, Mylvaganam R, Mount C, Onozato ML, Nahed BV, Wakimoto H, Curry WT, Iafrate AJ, Rivera MN, Frosch MP, Golub TR, Brastianos PK, Getz G, Patel AP, Monje M, Cahill DP, Rozenblatt-Rosen O, Louis DN, Bernstein BE, Regev A, Suvà ML. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science 2017; 355(6332): eaai8478

[29] Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4(1): 44–57

[30] Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009; 37(1): 1–13

[31] Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, Vivanco I, Lee JC, Huang JH, Alexander S, Du J, Kau T, Thomas RK, Shah K, Soto H, Perner S, Prensner J, Debiasi RM, Demichelis F, Hatton C, Rubin MA, Garraway LA, Nelson SF, Liau L, Mischel PS, Cloughesy TF, Meyerson M, Golub TA, Lander ES, Mellinghoff IK, Sellers WR. Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci USA 2007; 104(50): 20007–20012

[32] Tamayo P, Scanfeld D, Ebert BL, Gillette MA, Roberts CW, Mesirov JP. Metagene projection for cross-platform, cross-species characterization of global transcriptional states. Proc Natl Acad Sci USA 2007; 104(14): 5959–5964

[33] Zhang Y, Li J, Yi K, Feng J, Cong Z, Wang Z, Wei Y, Wu F, Cheng W, Samo AA, Salomoni P, Yang Q, Huang Y, Kang C, Jiang T, Fan X. Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma. Proc Natl Acad Sci USA 2019; 116(14): 6975–6984

[34] Talevich E, Shain AH, Botton T, Bastian BC. CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing. PLOS Comput Biol 2016; 12(4): e1004873

[35] Koboldt DC, Larson DE, Wilson RK. Using VarScan 2 for germline variant calling and somatic mutation detection. Curr Protoc Bioinformatics 2013; 44(1): 15.4.1–15.4.17

[36] Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018; 36(5): 411–420

[37] Yuan J, Levitin HM, Frattini V, Bush EC, Boyett DM, Samanamud J, Ceccarelli M, Dovas A, Zanazzi G, Canoll P, Bruce JN, Lasorella A, Iavarone A, Sims PA. Single-cell transcriptome analysis of lineage diversity in high-grade glioma. Genome Med 2018; 10(1): 57

[38] Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 2014; 34(36): 11929–11947

[39] Marques S, Zeisel A, Codeluppi S, van Bruggen D, Mendanha Falcão A, Xiao L, Li H, Häring M, Hochgerner H, Romanov RA, Gyllborg D, Muñoz Manchado A, La Manno G, Lönnerberg P, Floriddia EM, Rezayee F, Ernfors P, Arenas E, Hjerling-Leffler J, Harkany T, Richardson WD, Linnarsson S, Castelo-Branco G. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 2016; 352(6291): 1326–1329

[40] Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, Mulinyawe SB, Bohlen CJ, Adil A, Tucker A, Weissman IL, Chang EF, Li G, Grant GA, Hayden Gephart MG, Barres BA. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA 2016; 113(12): E1738–E1746

[41] RaviVMNeidertNWillPJosephKMaierJPKückelhausJVollmerLGoeldnerJMBehringerSPSchererFBoerriesMFolloMWeissTDelevDKernbachJFrancoPSchallnerNDierksCCarroMSHofmannUGFungCBeckJSankowskiRPrinzMSchnellOHenrikHeiland D. Lineage and spatial mapping of glioblastoma-associated immunity. bioRxiv, 2020: p. 2020.06.01.121467 doi:10.1101/2020.06.01.121467

[42] Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 2008; 28(1): 264–278

[43] Newman AM, Steen CB, Liu CL, Gentles AJ, Chaudhuri AA, Scherer F, Khodadoust MS, Esfahani MS, Luca BA, Steiner D, Diehn M, Alizadeh AA. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol 2019; 37(7): 773–782

[44] Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019; 47(D1): D607–D613

[45] Madhavan S, Zenklusen JC, Kotliarov Y, Sahni H, Fine HA, Buetow K. Rembrandt: helping personalized medicine become a reality through integrative translational research. Mol Cancer Res 2009; 7(2): 157–167

[46] Suzuki H, Aoki K, Chiba K, Sato Y, Shiozawa Y, Shiraishi Y, Shimamura T, Niida A, Motomura K, Ohka F, Yamamoto T, Tanahashi K, Ranjit M, Wakabayashi T, Yoshizato T, Kataoka K, Yoshida K, Nagata Y, Sato-Otsubo A, Tanaka H, Sanada M, Kondo Y, Nakamura H, Mizoguchi M, Abe T, Muragaki Y, Watanabe R, Ito I, Miyano S, Natsume A, Ogawa S. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 2015; 47(5): 458–468

[47] Cancer Genome Atlas Research Network; Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA, Rheinbay E, Miller CR, Vitucci M, Morozova O, Robertson AG, Noushmehr H, Laird PW, Cherniack AD, Akbani R, Huse JT, Ciriello G, Poisson LM, Barnholtz-Sloan JS, Berger MS, Brennan C, Colen RR, Colman H, Flanders AE, Giannini C, Grifford M, Iavarone A, Jain R, Joseph I, Kim J, Kasaian K, Mikkelsen T, Murray BA, O’Neill BP, Pachter L, Parsons DW, Sougnez C, Sulman EP, Vandenberg SR, Van Meir EG, von Deimling A, Zhang H, Crain D, Lau K, Mallery D, Morris S, Paulauskis J, Penny R, Shelton T, Sherman M, Yena P, Black A, Bowen J, Dicostanzo K, Gastier-Foster J, Leraas KM, Lichtenberg TM, Pierson CR, Ramirez NC, Taylor C, Weaver S, Wise L, Zmuda E, Davidsen T, Demchok JA, Eley G, Ferguson ML, Hutter CM, Mills Shaw KR, Ozenberger BA, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Ayala B, Baboud J, Chudamani S, Jensen MA, Liu J, Pihl T, Raman R, Wan Y, Wu Y, Ally A, Auman JT, Balasundaram M, Balu S, Baylin SB, Beroukhim R, Bootwalla MS, Bowlby R, Bristow CA, Brooks D, Butterfield Y, Carlsen R, Carter S, Chin L, Chu A, Chuah E, Cibulskis K, Clarke A, Coetzee SG, Dhalla N, Fennell T, Fisher S, Gabriel S, Getz G, Gibbs R, Guin R, Hadjipanayis A, Hayes DN, Hinoue T, Hoadley K, Holt RA, Hoyle AP, Jefferys SR, Jones S, Jones CD, Kucherlapati R, Lai PH, Lander E, Lee S, Lichtenstein L, Ma Y, Maglinte DT, Mahadeshwar HS, Marra MA, Mayo M, Meng S, Meyerson ML, Mieczkowski PA, Moore RA, Mose LE, Mungall AJ, Pantazi A, Parfenov M, Park PJ, Parker JS, Perou CM, Protopopov A, Ren X, Roach J, Sabedot TS, Schein J, Schumacher SE, Seidman JG, Seth S, Shen H, Simons JV, Sipahimalani P, Soloway MG, Song X, Sun H, Tabak B, Tam A, Tan D, Tang J, Thiessen N, Triche T Jr, Van Den Berg DJ, Veluvolu U, Waring S, Weisenberger DJ, Wilkerson MD, Wong T, Wu J, Xi L, Xu AW, Yang L, Zack TI, Zhang J, Aksoy BA, Arachchi H, Benz C, Bernard B, Carlin D, Cho J, DiCara D, Frazer S, Fuller GN, Gao J, Gehlenborg N, Haussler D, Heiman DI, Iype L, Jacobsen A, Ju Z, Katzman S, Kim H, Knijnenburg T, Kreisberg RB, Lawrence MS, Lee W, Leinonen K, Lin P, Ling S, Liu W, Liu Y, Liu Y, Lu Y, Mills G, Ng S, Noble MS, Paull E, Rao A, Reynolds S, Saksena G, Sanborn Z, Sander C, Schultz N, Senbabaoglu Y, Shen R, Shmulevich I, Sinha R, Stuart J, Sumer SO, Sun Y, Tasman N, Taylor BS, Voet D, Weinhold N, Weinstein JN, Yang D, Yoshihara K, Zheng S, Zhang W, Zou L, Abel T, Sadeghi S, Cohen ML, Eschbacher J, Hattab EM, Raghunathan A, Schniederjan MJ, Aziz D, Barnett G, Barrett W, Bigner DD, Boice L, Brewer C, Calatozzolo C, Campos B, Carlotti CG Jr, Chan TA, Cuppini L, Curley E, Cuzzubbo S, Devine K, DiMeco F, Duell R, Elder JB, Fehrenbach A, Finocchiaro G, Friedman W, Fulop J, Gardner J, Hermes B, Herold-Mende C, Jungk C, Kendler A, Lehman NL, Lipp E, Liu O, Mandt R, McGraw M, Mclendon R, McPherson C, Neder L, Nguyen P, Noss A, Nunziata R, Ostrom QT, Palmer C, Perin A, Pollo B, Potapov A, Potapova O, Rathmell WK, Rotin D, Scarpace L, Schilero C, Senecal K, Shimmel K, Shurkhay V, Sifri S, Singh R, Sloan AE, Smolenski K, Staugaitis SM, Steele R, Thorne L, Tirapelli DP, Unterberg A, Vallurupalli M, Wang Y, Warnick R, Williams F, Wolinsky Y, Bell S, Rosenberg M, Stewart C, Huang F, Grimsby JL, Radenbaugh AJ, Zhang J. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015; 372(26): 2481–2498 doi:10.1056/NEJMoa1402121 PMID:26061751

[48] Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, Morozova O, Newton Y, Radenbaugh A, Pagnotta SM, Anjum S, Wang J, Manyam G, Zoppoli P, Ling S, Rao AA, Grifford M, Cherniack AD, Zhang H, Poisson L, Carlotti CG Jr, Tirapelli DP, Rao A, Mikkelsen T, Lau CC, Yung WK, Rabadan R, Huse J, Brat DJ, Lehman NL, Barnholtz-Sloan JS, Zheng S, Hess K, Rao G, Meyerson M, Beroukhim R, Cooper L, Akbani R, Wrensch M, Haussler D, Aldape KD, Laird PW, Gutmann DH; TCGA Research Network, Noushmehr H, Iavarone A, Verhaak RG. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 2016; 164(3): 550–563

[49] Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJM, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 2014; 343(6167): 189–193

[50] Barthel FP, Johnson KC, Varn FS, Moskalik AD, Tanner G, Kocakavuk E, Anderson KJ, Abiola O, Aldape K, Alfaro KD, Alpar D, Amin SB, Ashley DM, Bandopadhayay P, Barnholtz-Sloan JS, Beroukhim R, Bock C, Brastianos PK, Brat DJ, Brodbelt AR, Bruns AF, Bulsara KR, Chakrabarty A, Chakravarti A, Chuang JH, Claus EB, Cochran EJ, Connelly J, Costello JF, Finocchiaro G, Fletcher MN, French PJ, Gan HK, Gilbert MR, Gould PV, Grimmer MR, Iavarone A, Ismail A, Jenkinson MD, Khasraw M, Kim H, Kouwenhoven MCM, LaViolette PS, Li M, Lichter P, Ligon KL, Lowman AK, Malta TM, Mazor T, McDonald KL, Molinaro AM, Nam DH, Nayyar N, Ng HK, Ngan CY, Niclou SP, Niers JM, Noushmehr H, Noorbakhsh J, Ormond DR, Park CK, Poisson LM, Rabadan R, Radlwimmer B, Rao G, Reifenberger G, Sa JK, Schuster M, Shaw BL, Short SC, Smitt PAS, Sloan AE, Smits M, Suzuki H, Tabatabai G, Van Meir EG, Watts C, Weller M, Wesseling P, Westerman BA, Widhalm G, Woehrer A, Yung WKA, Zadeh G, Huse JT, De Groot JF, Stead LF, Verhaak RGW, Barthel FP, Johnson KC, Varn FS, Moskalik AD, Tanner G, Kocakavuk E, Anderson KJ, Aldape K, Alfaro KD, Amin SB, Ashley DM, Bandopadhayay P, Barnholtz-Sloan JS, Beroukhim R, Bock C, Brastianos PK, Brat DJ, Brodbelt AR, Bulsara KR, Chakrabarty A, Chuang JH, Claus EB, Cochran EJ, Connelly J, Costello JF, Finocchiaro G, Fletcher MN, French PJ, Gan HK, Gilbert MR, Gould PV, Iavarone A, Ismail A, Jenkinson MD, Khasraw M, Kim H, Kouwenhoven MCM, LaViolette PS, Lichter P, Ligon KL, Lowman AK, Malta TM, McDonald KL, Molinaro AM, Nam DH, Ng HK, Niclou SP, Niers JM, Noushmehr H, Ormond DR, Park CK, Poisson LM, Rabadan R, Radlwimmer B, Rao G, Reifenberger G, Sa JK, Short SC, Smitt PAS, Sloan AE, Smits M, Suzuki H, Tabatabai G, Van Meir EG, Watts C, Weller M, Wesseling P, Westerman BA, Woehrer A, Yung WKA, Zadeh G, Huse JT, De Groot JF, Stead LF, Verhaak RGW; GLASS Consortium. Longitudinal molecular trajectories of diffuse glioma in adults. Nature 2019; 576(7785): 112–120

[51] Lee JK, Wang J, Sa JK, Ladewig E, Lee HO, Lee IH, Kang HJ, Rosenbloom DS, Camara PG, Liu Z, van Nieuwenhuizen P, Jung SW, Choi SW, Kim J, Chen A, Kim KT, Shin S, Seo YJ, Oh JM, Shin YJ, Park CK, Kong DS, Seol HJ, Blumberg A, Lee JI, Iavarone A, Park WY, Rabadan R, Nam DH. Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet 2017; 49(4): 594–599

[52] Draaisma K, Chatzipli A, Taphoorn M, Kerkhof M, Weyerbrock A, Sanson M, Hoeben A, Lukacova S, Lombardi G, Leenstra S, Hanse M, Fleischeuer R, Watts C, McAbee J, Angelopoulos N, Gorlia T, Golfinopoulos V, Kros JM, Verhaak RGW, Bours V, van den Bent MJ, McDermott U, Robe PA, French PJ. Molecular evolution of IDH wild-type glioblastomas treated with standard of care affects survival and design of precision medicine trials: a report from the EORTC 1542 study. J Clin Oncol 2020; 38(1): 81–99

[53] Gimple RC, Kidwell RL, Kim LJY, Sun T, Gromovsky AD, Wu Q, Wolf M, Lv D, Bhargava S, Jiang L, Prager BC, Wang X, Ye Q, Zhu Z, Zhang G, Dong Z, Zhao L, Lee D, Bi J, Sloan AE, Mischel PS, Brown JM, Cang H, Huan T, Mack SC, Xie Q, Rich JN. Glioma stem cell-specific superenhancer promotes polyunsaturated fatty-acid synthesis to support EGFR signaling. Cancer Discov 2019; 9(9): 1248–1267

[54] López-Juárez A, Titus HE, Silbak SH, Pressler JW, Rizvi TA, Bogard M, Bennett MR, Ciraolo G, Williams MT, Vorhees CV, Ratner N. Oligodendrocyte Nf1 controls aberrant notch activation and regulates myelin structure and behavior. Cell Rep 2017; 19(3): 545–557

[55] Kim H, Zheng S, Amini SS, Virk SM, Mikkelsen T, Brat DJ, Grimsby J, Sougnez C, Muller F, Hu J, Sloan AE, Cohen ML, Van Meir EG, Scarpace L, Laird PW, Weinstein JN, Lander ES, Gabriel S, Getz G, Meyerson M, Chin L, Barnholtz-Sloan JS, Verhaak RG. Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution. Genome Res 2015; 25(3): 316–327

[56] Yang C, Tan Y, Li S, Zhou J, Wang Q, Wang Y, Xie Y, Chen L, Li J, Fang C, Kang C. Genomic landscapes by multiregion sequencing combined with circulation tumor DNA detection contribute to molecular diagnosis in glioblastomas. Aging (Albany NY) 2019; 11(23): 11224–11243

[57] Yu K, Hu Y, Wu F, Guo Q, Qian Z, Hu W, Chen J, Wang K, Fan X, Wu X, Rasko JE, Fan X, Iavarone A, Jiang T, Tang F, Su XD. Surveying brain tumor heterogeneity by single-cell RNA-sequencing of multi-sector biopsies. Natl Sci Rev 2020; 7(8): 1306–1318

[58] Chaker Z, Codega P, Doetsch F. A mosaic world: puzzles revealed by adult neural stem cell heterogeneity. Wiley Interdiscip Rev Dev Biol 2016; 5(6): 640–658

[59] Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A. Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 2006; 26(30): 7907–7918

[60] Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA, Louis DN, Iafrate AJ. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011; 20(6): 810–817

[61] Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S, Leversha MA, Mikkelsen T, Brennan CW. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA 2012; 109(8): 3041–3046

[62] Laug D, Glasgow SM, Deneen B. A glial blueprint for gliomagenesis. Nat Rev Neurosci 2018; 19(7): 393–403

[63] Kougioumtzidou E, Shimizu T, Hamilton NB, Tohyama K, Sprengel R, Monyer H, Attwell D, Richardson WD. Signalling through AMPA receptors on oligodendrocyte precursors promotes myelination by enhancing oligodendrocyte survival. eLife 2017; 6: e28080

[64] LarsonVAZhangYBerglesDE. Electrophysiological properties of NG2(+) cells: matching physiological studies with gene expression profiles. Brain Res 2016; 1638(Pt B): 138–160 doi:10.1016/j.brainres.2015.09.010

[65] Castellan M, Guarnieri A, Fujimura A, Zanconato F, Battilana G, Panciera T, Sladitschek HL, Contessotto P, Citron A, Grilli A, Romano O, Bicciato S, Fassan M, Porcù E, Rosato A, Cordenonsi M, Piccolo S. Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in glioblastoma. Nat Can 2021; 2(2): 174–188

[66] Garofano L, Migliozzi S, Oh YT, D’Angelo F, Najac RD, Ko A, Frangaj B, Caruso FP, Yu K, Yuan J, Zhao W, Luisa Di Stefano A, Bielle F, Jiang T, Sims P, Suvà ML, Tang F, Su XD, Ceccarelli M, Sanson M, Lasorella A, Iavarone A. Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nat Can 2021; 2(2): 141–156

[67] Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, Agarwalla PK, Chheda MG, Campos B, Wang A, Brennan C, Ligon KL, Furnari F, Cavenee WK, Depinho RA, Chin L, Hahn WC. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 2012; 26(8): 756–784

[68] Pastrana E, Cheng LC, Doetsch F. Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proc Natl Acad Sci USA 2009; 106(15): 6387–6392

[69] Alcantara Llaguno S, Sun D, Pedraza AM, Vera E, Wang Z, Burns DK, Parada LF. Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction. Nat Neurosci 2019; 22(4): 545–555

Acknowledgements

We thank Drs. Chunsheng Kang and Robert S. Jack for insightful discussions of this project and critical reading of the manuscript. We would like to thank the Experimental Technology Center of Life Sciences, Beijing Normal University for the outstanding microscopic support. The results shown here are in part based upon data generated by the Chinese Glioma Genome Atlas, the TCGA Research Network, Ivy Glioblastoma Atlas Project, and the research teams of Drs. Do-Hyun Nam and Ken Aldape. The conception of this work has been made possible in part by the generous facility support from the Rausing Laboratory at Lund University, Sweden to Dr. Xiaolong Fan. The study was supported by the National Natural Science Foundation of China (Nos. 81773015 and 82072789), the National Key Research and Development Program of China (No. 2019YFE0108100), and the Erik Philip-Sörensen Foundation.

Compliance with ethics guidelines

Jiuyi Li. has been an employee of Gendya Biotechnology Ltd. Jing Feng, Zheng Zhao, Yanfei Wei, Zhaoshi Bao, Wei Zhang, Fan Wu, Guanzhang Li, Zhiyan Sun, Yanli Tan, Yunqiu Zhang, Zejun Duan, Xueling Qi, Kai Yu, Zhengmin Cong, Junjie Yang, Yaxin Wang, Yingyu Sun, Fuchou Tang, Xiaodong Su, Chuan Fang, Tao Jiang, and Xiaolong Fan declare no competing interests with respect to the research, authorship, and/or publication of this article. The use of patient materials and clinical data has been approved by the ethical committee of the respective hospitals and informed consent was obtained from all patients included in the study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0936-z and is accessible for authorized users.

RIGHTS & PERMISSIONS

2022 Higher Education Press