Chen, Ran

Gutmann, David H

Pan, Yuan

English

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Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2017The power of the fewRan ChenWashington University School of Medicine in St. LouisYuan PanWashington University School of Medicine in St. LouisDavid H. GutmannWashington University School of MedicineFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsThis Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in OpenAccess Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationChen, Ran; Pan, Yuan; and Gutmann, David H., ,"The power of the few." Genes & Development.31,12. 1177-1179. (2017).https://digitalcommons.wustl.edu/open_access_pubs/6018OUTLOOKThe power of the fewRan Chen, Yuan Pan, and David H. GutmannDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USAConverging evidence from numerous laboratories has re-vealed that malignant brain cancers are complex ecologi-cal systems composed of distinct cellular and acellularelements that collectively dictate glioblastoma biology.Our understanding of the individual contributions ofeach of these components is vital to the design of effectivetherapies against these cancers. In this issue of Genes &Development, Zanca and colleagues (pp. 1212–1227) dem-onstrate that one subpopulation of glioblastoma cellsexpressing a mutant epidermal growth factor receptor(EGFRvIII) is responsible for the survival of non-EGFR-vIII-expressing tumor cells as well as for evading molecu-larly targeted therapy.“Never in the field of human conflict was so much owedby so many to so few,” remarked Winston Churchill inhis praise of the contributions of the Allied airmen ofthe Royal Air Force during the Second World War. Inkeeping with the power of the few, Furnari and colleagues(Zanca et al. 2017) now report that a small population ofcancer cells in high-grade brain tumors (glioblastoma)can orchestrate the complex behavior of the entire tumor.Glioblastomas are deadly malignancies characterized bysignificant cellular and molecular heterogeneity. Assuch, malignant gliomas are composed of numerous dis-tinct cell types, including various neoplastic cells (gliomastem cells and neoplastic astrocytes) and nonneoplasticcells (endothelial cells, reactive astrocytes, and tumor-as-sociated monocytes). Moreover, even among the neoplas-tic cells, there exists considerable heterogeneity, withsubpopulations of cancer cells exhibiting specific tran-scriptomal profiles and expressing different mutations(Patel et al. 2014). One of these signature mutations in-volves the epidermal growth factor receptor (EGFR), inwhich several exons encoding sequences in the extracellu-lar domain of this receptor tyrosine kinase (RTK) are de-leted (EGFRvIII mutation), resulting in an aberrantlyfunctioning hyperactive EGFRmolecule. While EGFRvIIImutant glioblastoma cells comprise only 15% of the totalcancer cells in the tumor, they can serve as critical sculp-tors of the tumor microcosm.In this issue of Genes & Development, Zanca et al.(2017) demonstrate that EGFRvIII mutant glioblastomacells control the survival of wild-type (nonmutant)EGFR-expressing glioblastoma cells as well as provide aunique escape mechanism for evading therapeutic RTKinhibition. These studies identified interleukin-6 (IL-6),secreted by EGFRvIII mutant glioblastoma cells, as ananti-apoptotic effector responsible for attenuating glio-blastoma cell sensitivity to EGFR tyrosine kinase inhibi-tor (TKI) therapy. IL-6-mediated reduced EGFR TKIsensitivity has also been reported in non-small cell lungcancer, where EGFRTKI treatment triggers IL-6-mediatedfeedback through activation of Stat3 and downstream pro-survival genes (Lee et al. 2014). However, in glioblastoma,IL-6 also acts in a paracrine manner and binds to a com-mon IL-6 receptor (gp130) located on wild-type EGFR-ex-pressing glioblastoma cells. gp130 engagement by IL-6results inNF-kB activation, leading to expression of survi-vin, an anti-apoptotic protein. In this fashion, survivin in-duction protects glioblastoma cells from EGFR TKI-mediated apoptosis by providing an alternative way toactivate the mechanistic target of rapamycin (mTOR)complex, thus bypassing TKI suppression ofmTOR-medi-ated cell growth. Importantly, mutant EGFRvIII alsoincreases NFkB activity, resulting in elevated IL-6 tran-scription. Since NF-κB is responsible for both IL-6 produc-tion in EGFRvIII mutant glioblastoma cells and IL-6-mediated survivin induction in wild-type EGFR-express-ing tumor cells, inhibitors that blocked NF-κB activationwere sufficient to overcome TKI resistance in these braincancers.Collectively, the new findings described in this reportadd to an ever-deepening appreciation of how a smallnumber of cells in any given tumor can dictate the biolog-ical behavior of the entire cancer as well as how the glio-blastoma ecosystem is maintained through intersectingactivities mediated by one particular subpopulation ofdriver cells. The notion that an “Achilles’ heel” celltype exists in glioblastoma is exciting given the relativeresistance of these cancers to conventional and investiga-tional therapies. However, the dark side of this notion isthat numerous different cancer cell types could evolve[Keywords: tumor heterogeneity; glioblastoma; survivin; NF-κB; EGFR;IL-6]Corresponding author: gutmannd@wustl.eduArticle is online at http://www.genesdev.org/cgi/doi/10.1101/gad.303453.117.© 2017 Chen et al. This article is distributed exclusively by Cold SpringHarbor Laboratory Press for the first six months after the full-issue publi-cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Aftersix months, it is available under a Creative Commons License (At-tribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.GENES & DEVELOPMENT 31:1177–1179 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/17; www.genesdev.org 1177 Cold Spring Harbor Laboratory Press on August 7, 2017 - Published by genesdev.cshlp.orgDownloaded from within the tumor biome to influence overall glioblastomagrowth, thus creating opportunities to escape future de-signer chemotherapies.As a case in point, mutant EGFR expression in a smallpopulation of cancer cells can lead to profound changesin the glioblastoma ecosystem through a variety of dis-tinct, nonmutually exclusive mechanisms (Fig. 1). First,EGFRvIII has the capacity to transactivate other RTKsand, in doing so, drive tumor growth or limit therapeuticresponses (Huang et al. 2007; Pillay et al. 2009). For exam-ple, EGFRvIII transactivation of the hepatocyte growthfactor (HGF) receptor (MET) leads to resistance to rilotu-mumab, an antibody therapy that blocks tumor growthby neutralizing HGF and inhibiting HGF-mediated METsignaling (Pillay et al. 2009). Similarly, EGFRvIII receptorscan increase the activation of other RTKs through their in-appropriate retention at the cell surface (Greenall et al.2015) or by forming heterodimers that cause aberrantRTK activation and increasedmitogenic signaling (Green-all et al. 2015).Second, EGFRvIII expression can directly control thegrowth of other tumor cells in the glioma as a conse-quence of paracrine secretion of cytokines and growth fac-tors. In addition to IL-6 regulation of glioblastoma cellgrowth via gp130 receptor-mediated induction of survi-vin, EGFRvIII-expressing glioblastoma cells produce otherEGFR ligands, such as heparin-binding EGF (HB-EGF) andTGF-α (Ramnarain et al. 2006), each of which can act onthe wild-type EGFR receptor to drive tumor cell growth.Similarly, EGFR mutant glioblastoma cells increase IL-8production, which additionally enhances glioblastomastem cell growth. Moreover, chemokines (such as CCL5,secreted by glioblastoma cells) can create autocrinegrowth-promoting circuits in which tumor cells producetheir own mitogens in a self-stimulating manner to pro-mote cell survival (Pan et al. 2017).Third, cytokines and chemokines induced by mutantEGFR expression can alter the glioblastoma microenvi-ronment through the recruitment or activation of stromalcell types, such as endothelial cells and monocytes (mac-rophages and microglia). For example, mutant EGFR in-duces IL-8 and vascular endothelial growth factor(VEGF) secretion to increase angiogenesis in human glio-blastoma xenografts (Infanger et al. 2013). In addition,monocytes are recruited by chemokines (e.g., CX3CL1,CCL5, and CCL2) produced by glioblastoma cells. Thesetumor-associated microglia or macrophages are inducedto secrete IL-6, EGF, and likely othermitogens to establishparacrine relationships that further enhance glioblastomagrowth (Zhang et al. 2012).Taken together, the findings reported by Zanca et al.(2017) provide a conceptual framework in which the col-lective behavior of the tumor is defined by the adaptivemechanisms and circuits initiated and orchestrated by asmall population of tumor cells. With a greater under-standing of these interconnections, future therapiesmightemerge that target these bionetworks atmultiple nodes ofvulnerability.AcknowledgmentsD.H.G. is supported by a Research Program Award from the Na-tional Institute of Neurological Disorders and Stroke (1-R35-NS097211-01). Y.P. is supported by a McDonnell Foundation In-stitution fellowship grant.Figure 1. EGFRvIII is a master regulator ofglioblastoma ecosystem biology. EGFRvIIImutation in a small population of glioblastomacells can have profound effects on numerousdistinct cell types and thus influence the biol-ogy of the entire tumor. First, EGFRvIII expres-sion leads to EGFR activation and theengagement of downstream signaling path-ways and transcriptional programs, leading toincreased cell growth by either driving cell cy-cle progression or limiting programmed celldeath. Second, EGFRvIII expression can indi-rectly promote cell expansion through theelaboration of cytokines (e.g., IL-8 and VEGF)that engage tumor-associated monocytes(TAMs) or endothelial cells (angiogenesis), re-sulting in the elaboration of glioma-promotinggrowth factors (gliomagens). Third, EGFRvIIIexpression can increase glioma cell growthvia aberrant expression or transactivation ofother RTKs (e.g., c-MET). Fourth, EGFRvIII ex-pression can lead to the production of othergrowth factors (e.g., heparin-binding EGF [HB-EGF] and TGF-α), which can increase thegrowth of other glioblastoma cells in the tumorthrough activation of the wild-type EGFR. Last, EGFRvIII expression can trigger elevated levels of IL-6, which promotes cell survival bybinding to the IL-6 receptor (gp130).Chen et al.1178 GENES & DEVELOPMENT Cold Spring Harbor Laboratory Press on August 7, 2017 - Published by genesdev.cshlp.orgDownloaded from ReferencesGreenall SA, Donoghue JF, Van Sinderen M, Dubljevic V, Budi-man S, Devlin M, Street I, Adams TE, Johns TG. 2015. EGFR-vIII-mediated transactivation of receptor tyrosine kinases inglioma: mechanism and therapeutic implications. Oncogene34: 5277–5287.Huang PH,Mukasa A, Bonavia R, Flynn RA, Brewer ZE, CaveneeWK, Furnari FB, White FM. 2007. Quantitative analysis ofEGFRvIII cellular signaling networks reveals a combinatorialtherapeutic strategy for glioblastoma. Proc Natl Acad Sci 104:12867–12872.Infanger DW, Cho Y, Lopez BS, Mohanan S, Liu SC, Gursel D,Boockvar JA, Fischbach C. 2013. Glioblastoma stem cellsare regulated by interleukin-8 signaling in a tumoral perivas-cular niche. Cancer Res 73: 7079–7089.Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J. 2014. Drugresistance via feedback activation of Stat3 in oncogene-addict-ed cancer cells. Cancer Cell 26: 207–221.Pan Y, Smithson LJ, Ma Y, Hambardzumyan D, Gutmann DH.2017. Ccl5 establishes an autocrine high-grade glioma growthregulatory circuit critical for mesenchymal glioblastoma sur-vival. Oncotarget 8: 32977–32989.Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Waki-moto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, et al.2014. Single-cell RNA-seq highlights intratumoral heteroge-neity in primary glioblastoma. Science 344: 1396–1401.Pillay V, Allaf L, Wilding AL, Donoghue JF, Court NW, GreenallSA, Scott AM, Johns TG. 2009. The plasticity of oncogene ad-diction: implications for targeted therapies directed to recep-tor tyrosine kinases. Neoplasia 11: 448–458.Ramnarain DB, Park S, Lee DY, Hatanpaa KJ, Scoggin SO, Otu H,Libermann TA, Raisanen JM, Ashfaq R, Wong ET, et al. 2006.Differential gene expression analysis reveals generation of anautocrine loop by a mutant epidermal growth factor receptorin glioma cells. Cancer Res 66: 867–874.ZancaC, VillaGR, Benitez JA, ThorneAH, KogaT, D’AntonioM,Ikegami S,Ma J, Boyer AD, Banisadr A, et al. 2017. Glioblasto-ma cellular cross-talk converges on NF-κB to attenuate EGFRinhibitor sensitivity. Genes Dev (this issue). doi: 10.1101/gad.300079.117.Zhang J, Sarkar S, Cua R, Zhou Y, Hader W, Yong VW. 2012. Adialog between glioma and microglia that promotes tumor in-vasiveness through the CCL2/CCR2/interleukin-6 axis. Car-cinogenesis 33: 312–319.The power of the fewGENES & DEVELOPMENT 1179 Cold Spring Harbor Laboratory Press on August 7, 2017 - Published by genesdev.cshlp.orgDownloaded from  10.1101/gad.303453.117Access the most recent version at doi: 2017 31: 1177-1179 Genes Dev.  Ran Chen, Yuan Pan and David H. Gutmann  The power of the few  References   http://genesdev.cshlp.org/content/31/12/1177.full.html#related-urlsArticles cited in:   http://genesdev.cshlp.org/content/31/12/1177.full.html#ref-list-1This article cites 10 articles, 5 of which can be accessed free at:Related Content Genes Dev. June 15, 2017 31: 1212-1227Ciro Zanca, Genaro R. Villa, Jorge A. Benitez, et al.sensitivityGlioblastoma cellular cross-talk converges on NF-ºB to attenuate EGFR inhibitor  LicenseCommons Creative.http://creativecommons.org/licenses/by-nc/4.0/at Creative Commons License (Attribution-NonCommercial 4.0 International), as described ). After six months, it is available under ahttp://genesdev.cshlp.org/site/misc/terms.xhtmlsix months after the full-issue publication date (see This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the firstServiceEmail Alerting click here.right corner of the article orReceive free email alerts when new articles cite this article - sign up in the box at the topCollectionsTopic   (163 articles)  Cancer and Disease Models  Articles on similar topics can be found in the following collections  http://genesdev.cshlp.org/subscriptionsgo to: Genes & Development To subscribe to © 2017 Chen et al.; Published by Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press on August 7, 2017 - Published by genesdev.cshlp.orgDownloaded from 

The power of the few

Ran Chen

Yuan Pan

David H. Gutmann

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Genes & Development

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