Abstract
Mechanistic insight into signaling pathways downstream of surface receptors has been revolutionized with integrated cancer genomics. This has fostered current treatment modalities, namely immunotherapy, to capitalize on targeting key oncogenic signaling nodes downstream of a limited number of surface markers. Unfortunately, rudimentary mechanistic understanding of most other cell surface proteins has reduced the clinical utility of these markers. CD133 has reproducibly been shown to correlate with disease progression, recurrence, and poor overall survivorship in the malignant adult brain tumor, glioblastoma (GBM). Using several patient-derived CD133high and CD133low GBMs we describe intrinsic differences in determinants of stemness, which we owe to a CD133-AKT-Wnt signaling axis in which CD133 functions as a putative cell surface receptor for AKT-dependent Wnt activation. These findings may have implications for personalized oncology trials targeting PI3K/AKT or Wnt as both pathways may be activated independent of their canonical drivers, leading to treatment resistance and disease relapse.
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References
Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood. 1997;90:5002–12.
Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA. 2000;97:14720–5.
Cox CV, Diamanti P, Evely RS, Kearns PR, Blair A. Expression of CD133 on leukemia-initiating cells in childhood ALL. Blood. 2009;113:3287–96.
Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.
O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.
Shibahara I, Sonoda Y, Saito R, Kanamori M, Yamashita Y, Kumabe T, et al. The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence. Neuro-Oncol. 2013;15:1151–9.
Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, et al. Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res. 2008;14:123–9.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell. 2010;17:98–110.
Wei Y, Jiang Y, Zou F, Liu Y, Wang S, Xu N, et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells. Proc Natl Acad Sci USA. 2013;110:6829–34.
Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science. 2002;297:365–9.
Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR, et al. GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci. 2009;12:1390–7.
Rossi M, Magnoni L, Miracco C, Mori E, Tosi P, Pirtoli L, et al. beta-catenin and Gli1 are prognostic markers in glioblastoma. Cancer Biol Ther. 2011;11:753–61.
Zhang LY, Jiang LN, Li FF, Li H, Liu F, Gu Y, et al. Reduced beta-catenin expression is associated with good prognosis in Astrocytoma. Pathol Oncol Res. 2010;16:253–7.
Mak AB, Nixon AM, Kittanakom S, Stewart JM, Chen GI, Curak J, et al. Regulation of CD133 by HDAC6 promotes beta-catenin signaling to suppress cancer cell differentiation. Cell Rep. 2012;2:951–63.
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.
Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.
Hu B, Wang Q, Wang YA, Hua S, Sauve CG, Ong D, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell. 2016;167:1281–1295 e1218.
Ji H, Wang J, Nika H, Hawke D, Keezer S, Ge Q, et al. EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-Catenin. Mol cell. 2009;36:547–59.
Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan S, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013;45:253–61.
Pulvirenti T, Van Der Heijden M, Droms LA, Huse JT, Tabar V, Hall A. Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas. Cancer Res. 2011;71:7280–90.
Rheinbay E, Suva ML, Gillespie SM, Wakimoto H, Patel AP, Shahid M, et al. An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep. 2013;3:1567–79.
Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature. 2011;480:118–22.
Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, et al. FoxM1 promotes beta-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20:427–42.
Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV, et al. PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell. 2010;17:497–509.
Sastre-Perona A, Riesco-Eizaguirre G, Zaballos MA, Santisteban P. beta-catenin signaling is required for RAS-driven thyroid cancer through PI3K activation. Oncotarget. 2016;7:49435–49.
Lan X, Jorg DJ, Cavalli FMG, Richards LM, Nguyen LV, Vanner RJ, et al. Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy. Nature. 2017;549:227–32.
Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–401.
Hambardzumyan D, Squatrito M, Carbajal E, Holland EC. Glioma formation, cancer stem cells, and akt signaling. Stem Cell Rev. 2008;4:203–10.
Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet. 2000;25:55–7.
Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC. Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res. 2002;62:5551–8.
ter Haar E, Coll JT, Austen DA, Hsiao HM, Swenson L, Jain J. Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol. 2001;8:593–6.
Fuerer C, Nusse R. Lentiviral vectors to probe and manipulate the Wnt signaling pathway. PLoS ONE 2010;5:e9370.
Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15:943–53.
Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18:1373–85.
Wei W, Shin YS, Xue M, Matsutani T, Masui K, Yang H, et al. Single-cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma. Cancer Cell. 2016;29:563–73.
Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, et al. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet. 2000;9:27–34.
Ng SS, Mahmoudi T, Danenberg E, Bejaoui I, de Lau W, Korswagen HC, et al. Phosphatidylinositol 3-kinase signaling does not activate the wnt cascade. J Biol Chem. 2009;284:35308–13.
Fukumoto S, Hsieh CM, Maemura K, Layne MD, Yet SF, Lee KH, et al. Akt participation in the Wnt signaling pathway through Dishevelled. J Biol Chem. 2001;276:17479–83.
Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169:381–405.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.
Acknowledgements
B.M. is supported by a Canadian Institutes of Health Research Vanier Canada Graduate Scholarship. S.K.S. is supported by the Neurosurgical Research and Education Foundation and American Association of Neurological surgeons, Pediatric Section, the Ontario Institute for Cancer Research, and McMaster University Department of Surgery.
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BM, CV, CC, BWD, SKS conceptualized and designed the experiments. BM, CV, CC, MS, NS, NT performed experiments and acquired data. BM, CV, CC, BWD, SKS analyzed and interpreted data. BM wrote the manuscript with revisions contributed by CV, CC, BWD, and SKS. JM provided non-commercial reagents. JPP, NKK provided GBM study samples. BWD and SKS supervised the study. All authors reviewed results and commented on the manuscript.
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Manoranjan, B., Chokshi, C., Venugopal, C. et al. A CD133-AKT-Wnt signaling axis drives glioblastoma brain tumor-initiating cells. Oncogene 39, 1590–1599 (2020). https://doi.org/10.1038/s41388-019-1086-x
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DOI: https://doi.org/10.1038/s41388-019-1086-x
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