{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:38:50Z","timestamp":1787002730165,"version":"build-2736575974"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"20","license":[{"start":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T00:00:00Z","timestamp":1585008000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T00:00:00Z","timestamp":1585008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006313","name":"Barncancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006313","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008738","name":"Jeanssons Stiftelser","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003173","name":"Crafoordska Stiftelsen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003173","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007459","name":"Ragnar S\u00f6derbergs stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007459","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ollie & Elof Ericssons stiftelse G\u00f6sta Miltons donationsfond Stiftelsen Cancera"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Oncogene"],"published-print":{"date-parts":[[2020,5,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Glioblastoma multiforme is characterized in part by severe hypoxia associated with tumor necrosis. The cellular response to hypoxia can influence several properties of tumor cells associated with aggressive tumor growth, including metabolic adaptations and tumor cell migration and invasion. Here, we found that Delta Like Non-Canonical Notch Ligand 1 (DLK1) expression was elevated as compared with normal brain in a genetically engineered mouse model of glioma, and that\n                    <jats:italic>DLK1<\/jats:italic>\n                    expression increased with tumor grade in human glioma samples. DLK1 expression was highest in hypoxic and perivascular tumor areas, and we found that hypoxia induced the release and nuclear translocation of an intracellular fragment of DLK1 in murine glioma as well as in human glioma cultures. Release of the intracellular fragment was dependent on ADAM17 and Hypoxia-inducible Factor 1alpha and 2alpha (HIF-1alpha\/HIF-2alpha), as ADAM17 inhibitors and\n                    <jats:italic>HIF1A<\/jats:italic>\n                    \/\n                    <jats:italic>HIF2A<\/jats:italic>\n                    siRNA blocked DLK1 cleavage. Expression of a cleavable form of DLK1 amplified several hypoxia-induced traits of glioma cells such as colony formation, stem cell marker gene expression, a PI3K-pathway-mediated metabolic shift, and enhanced invasiveness. Effects of DLK1 were dependent on DLK1-cleavage by ADAM17, as expression of non-cleavable DLK1 could not replicate the DLK1-induced hypoxic phenotype. Finally, forced expression of DLK1 resulted in more invasive tumor growth in a PDGFB-induced glioma mouse model without affecting overall survival. Together, our findings suggest a previously undescribed role for DLK1 as an intracellular signaling molecule.\n                  <\/jats:p>","DOI":"10.1038\/s41388-020-1273-9","type":"journal-article","created":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T22:03:45Z","timestamp":1585001025000},"page":"4028-4044","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma"],"prefix":"10.1038","volume":"39","author":[{"given":"Elisa Stellaria","family":"Grassi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5965-5795","authenticated-orcid":false,"given":"Vasiliki","family":"Pantazopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5783-9347","authenticated-orcid":false,"given":"Alexander","family":"Pietras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,24]]},"reference":[{"key":"1273_CR1","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/nrc2818","volume":"10","author":"JT Huse","year":"2010","unstructured":"Huse JT, Holland EC. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010;10:319\u201331. https:\/\/doi.org\/10.1038\/nrc2818.","journal-title":"Nat Rev Cancer."},{"key":"1273_CR2","doi-asserted-by":"publisher","unstructured":"Bernstock JD, Mooney JH, Ilyas A, Chagoya G, Estevez-Ordonez D, Ibrahim A, et al. Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications. J Neurosurg. 2019;1\u20139. https:\/\/doi.org\/10.3171\/2019.5.JNS19364.","DOI":"10.3171\/2019.5.JNS19364"},{"key":"1273_CR3","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.trecan.2015.10.009","volume":"1","author":"D Hambardzumyan","year":"2015","unstructured":"Hambardzumyan D, Bergers G. Glioblastoma: defining tumor niches. Trends Cancer 2015;1:252\u201365. https:\/\/doi.org\/10.1016\/j.trecan.2015.10.009.","journal-title":"Trends Cancer"},{"key":"1273_CR4","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.molcel.2010.09.022","volume":"40","author":"AJ Majmundar","year":"2010","unstructured":"Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294\u2013309. https:\/\/doi.org\/10.1016\/j.molcel.2010.09.022.","journal-title":"Mol Cell."},{"key":"1273_CR5","doi-asserted-by":"publisher","first-page":"1852","DOI":"10.1038\/sj.onc.1209219","volume":"25","author":"D Yin","year":"2006","unstructured":"Yin D, Xie D, Sakajiri S, Miller CW, Zhu H, Popoviciu ML, et al. DLK1: increased expression in gliomas and associated with oncogenic activities. Oncogene. 2006;25:1852\u201361. https:\/\/doi.org\/10.1038\/sj.onc.1209219.","journal-title":"Oncogene."},{"key":"1273_CR6","doi-asserted-by":"publisher","first-page":"9271","DOI":"10.1158\/0008-5472.CAN-09-1605","volume":"69","author":"Y Kim","year":"2009","unstructured":"Kim Y, Lin Q, Zelterman D, Yun Z. Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity. Cancer Res. 2009;69:9271\u201380. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-1605.","journal-title":"Cancer Res."},{"key":"1273_CR7","doi-asserted-by":"publisher","first-page":"6040","DOI":"10.1158\/0008-5472.CAN-05-4528","volume":"66","author":"B Dekel","year":"2006","unstructured":"Dekel B, Metsuyanim S, Schmidt-Ott KM, Fridman E, Jacob-Hirsch J, Simon A, et al. Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney. Cancer Res. 2006;66:6040\u20139. https:\/\/doi.org\/10.1158\/0008-5472.CAN-05-4528.","journal-title":"Cancer Res."},{"key":"1273_CR8","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1016\/j.eururo.2008.03.006","volume":"54","author":"JA Ceder","year":"2008","unstructured":"Ceder JA, Jansson L, Helczynski L, Abrahamsson P-A. Delta-like 1 (Dlk-1), a novel marker of prostate basal and candidate epithelial stem cells, is downregulated by notch signalling in intermediate\/transit amplifying cells of the human prostate. Eur Urol. 2008;54:1344\u201353. https:\/\/doi.org\/10.1016\/j.eururo.2008.03.006.","journal-title":"Eur Urol"},{"key":"1273_CR9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091509","volume":"9","author":"L Li","year":"2014","unstructured":"Li L, Tan J, Zhang Y, Han N, Di X, Xiao T, et al. DLK1 promotes lung cancer cell invasion through upregulation of MMP9 expression depending on Notch signaling. PLoS One Public Libr Sci. 2014;9:e91509. https:\/\/doi.org\/10.1371\/journal.pone.0091509.","journal-title":"PLoS One Public Libr Sci"},{"key":"1273_CR10","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1016\/j.bbadis.2012.02.003","volume":"1822","author":"FA Falix","year":"2012","unstructured":"Falix FA, Aronson DC, Lamers WH, Gaemers IC. Possible roles of DLK1 in the Notch pathway during development and disease. Biochim Biophys Acta. 2012;1822:988\u201395. https:\/\/doi.org\/10.1016\/j.bbadis.2012.02.003.","journal-title":"Biochim Biophys Acta."},{"key":"1273_CR11","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nature10229","volume":"475","author":"SR Ferr\u00f3n","year":"2011","unstructured":"Ferr\u00f3n SR, Charalambous M, Radford E, McEwen K, Wildner H, Hind E, et al. Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature. 2011;475:381\u20135. https:\/\/doi.org\/10.1038\/nature10229.","journal-title":"Nature."},{"key":"1273_CR12","doi-asserted-by":"publisher","first-page":"5421","DOI":"10.1128\/MCB.02437-05","volume":"26","author":"Y Wang","year":"2006","unstructured":"Wang Y, Sul HS. Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation. Mol Cell Biol. 2006;26:5421\u201335. https:\/\/doi.org\/10.1128\/MCB.02437-05.","journal-title":"Mol Cell Biol"},{"key":"1273_CR13","doi-asserted-by":"publisher","unstructured":"Traustad\u00f3ttir G\u00c1, Lagoni LV, Ankerstjerne LBS, Bisgaard HC, Jensen CH, Andersen DC. The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1)is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms. Cytokine Growth Factor Rev. 2019;17\u201327. https:\/\/doi.org\/10.1016\/j.cytogfr.2019.03.006.","DOI":"10.1016\/j.cytogfr.2019.03.006"},{"key":"1273_CR14","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.cmet.2009.01.013","volume":"9","author":"Y Wang","year":"2009","unstructured":"Wang Y, Sul HS. Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9. Cell Metab. 2009;9:287\u2013302. https:\/\/doi.org\/10.1016\/j.cmet.2009.01.013.","journal-title":"Cell Metab."},{"key":"1273_CR15","doi-asserted-by":"publisher","first-page":"79.","DOI":"10.3389\/fendo.2013.00079","volume":"4","author":"CS Hudak","year":"2013","unstructured":"Hudak CS, Sul HS. Pref-1 a gatekeeper of adipogenesis. Front Endocrinol (Lausanne) 2013;4:79. https:\/\/doi.org\/10.3389\/fendo.2013.00079.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"1273_CR16","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/j.celrep.2018.09.086","volume":"25","author":"O Gulyaeva","year":"2018","unstructured":"Gulyaeva O, Nguyen H, Sambeat A, Heydari K, Sul HS. Sox9-Meis1 inactivation is required for adipogenesis, advancing pref-1+ to PDGFR\u03b1+ cells. Cell Rep. 2018;25:1002\u2013.e4. https:\/\/doi.org\/10.1016\/j.celrep.2018.09.086.","journal-title":"Cell Rep."},{"key":"1273_CR17","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.ijbiomac.2017.01.067","volume":"97","author":"G\u00c1 Traustad\u00f3ttir","year":"2017","unstructured":"Traustad\u00f3ttir G\u00c1, Jensen CH, Garcia Ramirez JJ, Beck HC, Sheikh SP, Andersen DC. The non-canonical NOTCH1 ligand Delta-like 1 homolog (DLK1) self interacts in mammals. Int J Biol Macromol. 2017;97:460\u20137. https:\/\/doi.org\/10.1016\/j.ijbiomac.2017.01.067.","journal-title":"Int J Biol Macromol."},{"key":"1273_CR18","doi-asserted-by":"publisher","first-page":"3480","DOI":"10.1128\/mcb.00057-10","volume":"30","author":"Y Wang","year":"2010","unstructured":"Wang Y, Zhao L, Smas C, Sul HS. Pref-1 interacts with fibronectin to inhibit adipocyte differentiation. Mol Cell Biol Am Soc Microbiol. 2010;30:3480\u201392. https:\/\/doi.org\/10.1128\/mcb.00057-10.","journal-title":"Mol Cell Biol Am Soc Microbiol"},{"key":"1273_CR19","doi-asserted-by":"publisher","first-page":"3675","DOI":"10.1101\/gad.12.23.3675","volume":"12","author":"EC Holland","year":"1998","unstructured":"Holland EC, Hively WP, DePinho RA, Varmus HE. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 1998;12:3675\u201385. https:\/\/doi.org\/10.1101\/gad.12.23.3675.","journal-title":"Genes Dev."},{"key":"1273_CR20","doi-asserted-by":"publisher","unstructured":"Johansson E, Grassi ES, Pantazopoulou V, Tong B, Lindgren D, Berg TJ, et al. CD44 Interacts with HIF-2\u03b1 to modulate the hypoxic phenotype of perinecrotic and perivascular glioma cells. Cell Rep. 2017;20. https:\/\/doi.org\/10.1016\/j.celrep.2017.07.049.","DOI":"10.1016\/j.celrep.2017.07.049"},{"key":"1273_CR21","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.cell.2015.12.028","volume":"164","author":"M Ceccarelli","year":"2016","unstructured":"Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell Cell Press. 2016;164:550\u201363. https:\/\/doi.org\/10.1016\/j.cell.2015.12.028.","journal-title":"Cell Cell Press"},{"key":"1273_CR22","doi-asserted-by":"publisher","unstructured":"Zhao Z, Zhang K, Wang Q, Li G, Zeng F, Zhang Y, et al. Chinese Glioma Genome Atlas (CGGA): a comprehensive resource with functional genomic data for chinese glioma patients. bioRxiv. 2020. https:\/\/doi.org\/10.1101\/2020.01.20.911982.","DOI":"10.1101\/2020.01.20.911982"},{"key":"1273_CR23","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/j.ebiom.2015.08.026","volume":"2","author":"Y Xie","year":"2015","unstructured":"Xie Y, Bergstr\u00f6m T, Jiang Y, Johansson P, Marinescu VD, Lindberg N, et al. The human glioblastoma cell culture resource: validated cell models representing all molecular subtypes. EBioMedicine. 2015;2:1351\u201363. https:\/\/doi.org\/10.1016\/j.ebiom.2015.08.026.","journal-title":"EBioMedicine."},{"key":"1273_CR24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036134","volume":"7","author":"C Villanueva","year":"2012","unstructured":"Villanueva C, Jacquier S, de Roux N. DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons. PLoS One Public Libr Sci. 2012;7:e36134. https:\/\/doi.org\/10.1371\/journal.pone.0036134.","journal-title":"PLoS One Public Libr Sci"},{"key":"1273_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.318","volume":"7","author":"S Jawhari","year":"2016","unstructured":"Jawhari S, Ratinaud M-H, Verdier M. Glioblastoma, hypoxia and autophagy: a survival-prone \u201cm\u00e9nage-\u00e0-trois\u201d. Cell Death Dis Nat Publ Group. 2016;7:e2434. https:\/\/doi.org\/10.1038\/cddis.2016.318.","journal-title":"Cell Death Dis Nat Publ Group"},{"key":"1273_CR26","doi-asserted-by":"publisher","first-page":"3547","DOI":"10.3892\/mmr.2018.9375","volume":"18","author":"Z Zhang","year":"2018","unstructured":"Zhang Z, Yao L, Yang J, Wang Z, Du G. PI3K\/Akt and HIF\u20111 signaling pathway in hypoxia\u2011ischemia (review). Mol Med Rep. 2018;18:3547\u201354. https:\/\/doi.org\/10.3892\/mmr.2018.9375.","journal-title":"Mol Med Rep."},{"key":"1273_CR27","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1172\/JCI82058","volume":"125","author":"Z Yun","year":"2015","unstructured":"Yun Z, Glazer PM. Tumor suppressor p53 stole the AKT in hypoxia. J Clin Invest. 2015;125:2264\u20136. https:\/\/doi.org\/10.1172\/JCI82058.","journal-title":"J Clin Invest."},{"key":"1273_CR28","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","volume":"169","author":"BD Manning","year":"2017","unstructured":"Manning BD, Toker A. AKT\/PKB signaling: navigating the network. Cell. 2017;169:381\u2013405. https:\/\/doi.org\/10.1016\/j.cell.2017.04.001.","journal-title":"Cell."},{"key":"1273_CR29","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1111\/bpa.12307","volume":"25","author":"K Masui","year":"2015","unstructured":"Masui K, Cavenee WK, Mischel PS. mTORC2 and metabolic reprogramming in GBM: at the interface of genetics and environment. Brain Pathol. 2015;25:755\u20139. https:\/\/doi.org\/10.1111\/bpa.12307.","journal-title":"Brain Pathol."},{"key":"1273_CR30","doi-asserted-by":"publisher","first-page":"43.","DOI":"10.3389\/fcell.2017.00043","volume":"5","author":"M Strickland","year":"2017","unstructured":"Strickland M, Stoll EA. Metabolic reprogramming in glioma. Front Cell Dev Biol. 2017;5:43. https:\/\/doi.org\/10.3389\/fcell.2017.00043.","journal-title":"Front Cell Dev Biol"},{"key":"1273_CR31","doi-asserted-by":"publisher","first-page":"3892","DOI":"10.1158\/0008-5472.CAN-03-2904","volume":"64","author":"RL Elstrom","year":"2004","unstructured":"Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64:3892\u20139. https:\/\/doi.org\/10.1158\/0008-5472.CAN-03-2904.","journal-title":"Cancer Res."},{"key":"1273_CR32","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s11010-009-0154-x","volume":"331","author":"J Ma","year":"2009","unstructured":"Ma J, Sawai H, Ochi N, Matsuo Y, Xu D, Yasuda A, et al. PTEN regulate angiogenesis through PI3K\/Akt\/VEGF signaling pathway in human pancreatic cancer cells. Mol Cell Biochem. 2009;331:161\u201371. https:\/\/doi.org\/10.1007\/s11010-009-0154-x.","journal-title":"Mol Cell Biochem."},{"key":"1273_CR33","unstructured":"Cho SJ, Chae MJ, Shin BK, Kim HK, Kim A. Akt- and MAPK-mediated activation and secretion of MMP-9 into stroma in breast cancer cells upon heregulin treatment. Mol Med Rep. 2008;1:83\u20138. http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21479382."},{"key":"1273_CR34","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1126\/science.aaf2666","volume":"360","author":"RB Puchalski","year":"2018","unstructured":"Puchalski RB, Shah N, Miller J, Dalley R, Nomura SR, Yoon J-G, et al. An anatomic transcriptional atlas of human glioblastoma. Science. 2018;360:660\u20133. https:\/\/doi.org\/10.1126\/science.aaf2666.","journal-title":"Science."},{"key":"1273_CR35","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1074\/jbc.M605451200","volume":"282","author":"E Dyczynska","year":"2007","unstructured":"Dyczynska E, Sun D, Yi H, Sehara-Fujisawa A, Blobel CP, Zolkiewska A. Proteolytic processing of delta-like 1 by ADAM proteases. J Biol Chem. 2007;282:436\u201344. https:\/\/doi.org\/10.1074\/jbc.M605451200.","journal-title":"J Biol Chem."},{"key":"1273_CR36","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S1097-2765(00)80417-7","volume":"5","author":"C Brou","year":"2000","unstructured":"Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, et al. A novel proteolytic cleavage involved in notch signaling. Mol Cell 2000;5:207\u201316. https:\/\/doi.org\/10.1016\/S1097-2765(00)80417-7.","journal-title":"Mol Cell"},{"key":"1273_CR37","doi-asserted-by":"publisher","unstructured":"Pelullo M, Nardozza F, Zema S, Quaranta R, Nicoletti C, Besharat ZM, et al. Kras\/ADAM17-dependent Jag1-ICD reverse signalling sustains colorectal cancer progression and chemoresistance. Cancer Res. 2019. https:\/\/doi.org\/10.1158\/0008-5472.CAN-19-0145.","DOI":"10.1158\/0008-5472.CAN-19-0145"},{"key":"1273_CR38","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1083\/jcb.200310024","volume":"165","author":"O Nagano","year":"2004","unstructured":"Nagano O, Murakami D, Hartmann D, De Strooper B, Saftig P, Iwatsubo T, et al. Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca(2+) influx and PKC activation. J Cell Biol. 2004;165:893\u2013902. https:\/\/doi.org\/10.1083\/jcb.200310024.","journal-title":"J Cell Biol."},{"key":"1273_CR39","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.stem.2014.01.005","volume":"14","author":"A Pietras","year":"2014","unstructured":"Pietras A, Katz AM, Ekstr\u00f6m EJ, Wee B, Halliday JJ, Pitter KL, et al. Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell. 2014;14:357\u201369. https:\/\/doi.org\/10.1016\/j.stem.2014.01.005.","journal-title":"Cell Stem Cell."},{"key":"1273_CR40","doi-asserted-by":"publisher","first-page":"4241","DOI":"10.1074\/jbc.M307974200","volume":"279","author":"G Weskamp","year":"2004","unstructured":"Weskamp G, Schl\u00f6ndorff J, Lum L, Becherer JD, Kim T-W, Saftig P, et al. Evidence for a critical role of the tumor necrosis factor alpha convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR). J Biol Chem. 2004;279:4241\u20139. https:\/\/doi.org\/10.1074\/jbc.M307974200.","journal-title":"J Biol Chem."},{"key":"1273_CR41","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.yexcr.2018.08.002","volume":"371","author":"B Tong","year":"2018","unstructured":"Tong B, Pantazopoulou V, Johansson E, Pietras A. The p75 neurotrophin receptor enhances HIF-dependent signaling in glioma. Exp Cell Res. 2018;371:122\u20139. https:\/\/doi.org\/10.1016\/j.yexcr.2018.08.002.","journal-title":"Exp Cell Res."},{"key":"1273_CR42","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.yexcr.2004.10.001","volume":"303","author":"V Baladr\u00f3n","year":"2005","unstructured":"Baladr\u00f3n V, Ruiz-Hidalgo MJ, Nueda ML, D\u00edaz-Guerra MJM, Garc\u00eda-Ram\u00edrez JJ, Bonvini E, et al. Dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. Exp Cell Res 2005;303:343\u201359. https:\/\/doi.org\/10.1016\/j.yexcr.2004.10.001.","journal-title":"Exp Cell Res"},{"key":"1273_CR43","doi-asserted-by":"publisher","first-page":"3201","DOI":"10.1038\/s41388-018-0658-5","volume":"38","author":"C-C Huang","year":"2019","unstructured":"Huang C-C, Cheng S-H, Wu C-H, Li W-Y, Wang J-S, Kung M-L, et al. Delta-like 1 homologue promotes tumorigenesis and epithelial-mesenchymal transition of ovarian high-grade serous carcinoma through activation of Notch signaling. Oncogene. 2019;38:3201\u201315. https:\/\/doi.org\/10.1038\/s41388-018-0658-5.","journal-title":"Oncogene."},{"key":"1273_CR44","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1111\/j.1349-7006.2007.00440.x","volume":"98","author":"X Zheng","year":"2007","unstructured":"Zheng X, Jiang F, Katakowski M, Kalkanis SN, Hong X, Zhang X, et al. Inhibition of ADAM17 reduces hypoxia-induced brain tumor cell invasiveness. Cancer Sci. 2007;98:674\u201384. https:\/\/doi.org\/10.1111\/j.1349-7006.2007.00440.x.","journal-title":"Cancer Sci."},{"key":"1273_CR45","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1002\/path.2304","volume":"214","author":"A Pietras","year":"2008","unstructured":"Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S, et al. High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol. 2008;214:482\u20138. https:\/\/doi.org\/10.1002\/path.2304.","journal-title":"J Pathol"},{"key":"1273_CR46","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.stem.2009.01.007","volume":"4","author":"A-M Bleau","year":"2009","unstructured":"Bleau A-M, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW, et al. PTEN\/PI3K\/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell. 2009;4:226\u201335. https:\/\/doi.org\/10.1016\/j.stem.2009.01.007.","journal-title":"Cell Stem Cell."},{"key":"1273_CR47","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/neuonc\/now247","volume":"19","author":"RL Bowman","year":"2017","unstructured":"Bowman RL, Wang Q, Carro A, Verhaak RGW, Squatrito M. GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol. 2017;19:139\u201341. https:\/\/doi.org\/10.1093\/neuonc\/now247.","journal-title":"Neuro Oncol."}],"container-title":["Oncogene"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41388-020-1273-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41388-020-1273-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41388-020-1273-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T17:20:46Z","timestamp":1684603246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41388-020-1273-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,24]]},"references-count":47,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2020,5,14]]}},"alternative-id":["1273"],"URL":"https:\/\/doi.org\/10.1038\/s41388-020-1273-9","relation":{},"ISSN":["0950-9232","1476-5594"],"issn-type":[{"value":"0950-9232","type":"print"},{"value":"1476-5594","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,24]]},"assertion":[{"value":"21 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}