Abstract
Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wen PY, Kesari S . Malignant gliomas in adults. N Engl J Med 2008; 359: 492–507.
Johannessen TC, Bjerkvig R . Molecular mechanisms of temozolomide resistance in glioblastoma multiforme. Expert Review of Anticancer Therapy 2012; 12: 635–642.
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444: 756–760.
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: 5821–5828.
Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 2004; 23: 9392–9400.
Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004; 64: 7011–7021.
Germano I, Swiss V, Casaccia P . Primary brain tumors, neural stem cell, and brain tumor cancer cells: Where is the link? Neuropharmacology 2010; 58: 903–910.
Visvader JE, Lindeman GJ . Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8: 755–768.
Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011; 20: 810–817.
Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proceedings of the National Academy of Sciences of the United States of America 2013; 110: 4009–4014.
Sottoriva A, Spiteri I, Shibata D, Curtis C, Tavare S . Single-molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization. Cancer research 2013; 73: 41–49.
Fareh M, Turchi L, Virolle V, Debruyne D, Almairac F, de-la-Forest Divonne S et al. The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network. Cell Death and Differentiation 2012; 19: 232–244.
Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N et al. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 2010; 28: 5–16.
Ligon KL, Huillard E, Mehta S, Kesari S, Liu H, Alberta JA et al. Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 2007; 53: 503–517.
Gong A, Huang S . FoxM1 and Wnt/beta-catenin signaling in glioma stem cells. Cancer Research 2012; 72: 5658–5662.
Upadhyay G, Goessling W, North TE, Xavier R, Zon LI, Yajnik V . Molecular association between beta-catenin degradation complex and Rac guanine exchange factor DOCK4 is essential for Wnt/beta-catenin signaling. Oncogene 2008; 27: 5845–5855.
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.
Patru C, Romao L, Varlet P, Coulombel L, Raponi E, Cadusseau J et al. CD133, CD15/SSEA-1, CD34 or side populations do not resume tumor-initiating properties of long-term cultured cancer stem cells from human malignant glio-neuronal tumors. BMC Cancer 2010; 10: 66.
Turchi L, Debruyne DN, Almairac F, Virolle V, Fareh M, Neirijnck Y et al. Tumorigenic Potential of miR-18A* in Glioma Initiating Cells Requires NOTCH-1 Signaling. Stem Cells 2013; 31 (7): 1252–1265.
Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A 1999; 96: 5522–5527.
Piccirillo SG, Vescovi AL . Bone morphogenetic proteins regulate tumorigenicity in human glioblastoma stem cells. Ernst Schering Found Symp Proc 2006; 5: 59–81.
Lee M, Nam EJ, Kim SW, Kim S, Kim JH, Kim YT . Prognostic impact of the cancer stem cell-related marker NANOG in ovarian serous carcinoma. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society 2012; 22: 1489–1496.
Meng HM, Zheng P, Wang XY, Liu C, Sui HM, Wu SJ et al. Overexpression of nanog predicts tumor progression and poor prognosis in colorectal cancer. Cancer Biology & Therapy 2010; 9: 295–302.
Nagata T, Shimada Y, Sekine S, Hori R, Matsui K, Okumura T et al. Prognostic significance of NANOG and KLF4 for breast cancer. Breast Cancer 2014; 21: 96–101.
Korur S, Huber RM, Sivasankaran B, Petrich M, Morin Jr P, Hemmings BA et al. GSK3beta regulates differentiation and growth arrest in glioblastoma. PLoS One 2009; 4: e7443.
Kotliarova S, Pastorino S, Kovell LC, Kotliarov Y, Song H, Zhang W et al. Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation. Cancer Research 2008; 68: 6643–6651.
Farhana L, Dawson MI, Das JK, Murshed F, Xia Z, Hadden TJ et al. Adamantyl Retinoid-Related Molecules Induce Apoptosis in Pancreatic Cancer Cells by Inhibiting IGF-1R and Wnt/beta-Catenin Pathways. Journal of Oncology 2012; 2012: 796729.
Hallett RM, Kondratyev MK, Giacomelli AO, Nixon AM, Girgis-Gabardo A, Ilieva D et al. Small molecule antagonists of the Wnt/beta-catenin signaling pathway target breast tumor-initiating cells in a Her2/Neu mouse model of breast cancer. PLoS One 2012; 7: e33976.
Kleppe M, Levine RL . Targeting beta-catenin in CML: leukemia stem cells beware!. Cell Stem Cell 2012; 10: 351–353.
Mills CN, Nowsheen S, Bonner JA, Yang ES . Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors. Frontiers in Molecular Neuroscience 2011; 4: 47.
LaFramboise T, Dewal N, Wilkins K, Pe'er I, Freedman ML . Allelic selection of amplicons in glioblastoma revealed by combining somatic and germline analysis. PLoS Genetics 2010; 6: e1001086.
Dahan P, Martinez Gala J, Delmas C, Monferran S, Malric L, Zentkowski D et al. Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance. Cell Death & Disease 2014; 5: e1543.
Acknowledgements
This work was supported by grants from the Association pour la Recherche sur le Cancer (subvention 3161), Association Sauvons Laura, ADerTU, Association Dimitri Bessière, Agence Nationale pour la Recherche (ANR Jeunes Chercheurs, Jeunes Chercheuses, «GLIOMIRSTEM project»), Fondation de France, ARC projet (SFI20111203773), INCA PLBIO2012, ITMO CANCER plan cancer, INSERM, UNSA. We thank A Borderie, S Bestrée, C Hagnere, F Frassinetti, S Rekima, AC Peyron and F Keslair for their technical assistance and C. Colin for the statistical analysis. We thank Doctor Enzo Lalli for providing the PKF115-584 inhibitor and Doctor Andreas Schedl for the mYhBCATf and the TopFlash reporter plasmid. We thank Doctor Ellen Van Obberghen-Schilling for grammatical corrections.
Author contributions
DND, LT, FBV and TV designed the research. DND, FA, LT, FBV, VV, NBK performed the experiments. DND, NBK, DFB, FB, MF, FA, LT, FBV, PL and PV analyzed the data. DND, LT, DF, PP, FBV, MPJ, HC and TV discussed the data. DND and MPJ has corrected the manuscript. TV wrote the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Debruyne, D., Turchi, L., Burel-Vandenbos, F. et al. DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression. Oncogene 37, 241–254 (2018). https://doi.org/10.1038/onc.2017.323
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2017.323
This article is cited by
-
The adaptive transition of glioblastoma stem cells and its implications on treatments
Signal Transduction and Targeted Therapy (2021)
-
DOCK6 promotes chemo- and radioresistance of gastric cancer by modulating WNT/β-catenin signaling and cancer stem cell traits
Oncogene (2020)
-
Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells
Acta Neuropathologica Communications (2019)
-
miR-302a inhibits human HepG2 and SMMC-7721 cells proliferation and promotes apoptosis by targeting MAP3K2 and PBX3
Scientific Reports (2019)
-
Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness
Acta Neuropathologica (2018)