nach oben

Erschienen in:

05.01.2022 | Laboratory Investigation

Pediatric brain tumor cell lines exhibit miRNA-depleted, Y RNA-enriched extracellular vesicles

verfasst von: Setty M. Magaña, Timothy E. Peterson, Jared E. Evans, Paul A. Decker, Vernadette Simon, Jeanette E. Eckel-Passow, David J. Daniels, Ian F. Parney

Erschienen in: Journal of Neuro-Oncology | Ausgabe 2/2022

Einloggen, um Zugang zu erhalten

Abstract

Background

Medulloblastoma (MB) and diffuse infiltrative pontine glioma (DIPG) are malignant pediatric tumors. Extracellular vesicles (EVs) and their bioactive cargoes have been implicated in tumorigenesis. Most studies have focused on adult tumors, therefore the role of EVs and the noncoding RNA (ncRNA) landscape in pediatric brain tumors is not fully characterized. The overall aim of this pilot study was to isolate EVs from MB and DIPG patient-derived cell lines and to explore the small ncRNA transcriptome.

Methods

EVs from 3 DIPG and 4 MB patient-derived cell lines were analyzed. High-throughput next generation sequencing interrogated the short non-coding RNA (ncRNA) transcriptome. Known and novel miRNAs were quantified. Differential expression analysis, in silico target prediction, and functional gene enrichment were performed.

Results

EV secretomes from MB and DIPG patient-derived cell lines demonstrated discrete ncRNA biotypes. Notably, miRNAs were depleted and Y RNAs were enriched in EV samples. Hierarchical cluster analysis revealed high discrimination in miRNA expression between DIPG and MB cell lines and RNA-Seq identified novel miRNAs not previously implicated in MB or DIPG pathogenesis. Known and putative target genes of dysregulated miRNAs were identified. Functional annotation analysis of the target genes for differentially expressed EV-and parental-derived miRNAs revealed significant cancer-related pathway involvement.

Conclusions

This hypothesis-generating study demonstrated that pediatric brain tumor-derived cell lines secrete EVs comprised of various ncRNA cargoes. Validation of these findings in patient samples may provide new insights into the pediatric brain tumor microenvironment and identification of novel therapeutic candidates.

Nur mit Berechtigung zugänglich

Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS (2018) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol 20:iv1–iv86. https://doi.org/10.1093/neuonc/noy131CrossRefPubMedPubMedCentral

Lin T, Prados M (2017) Pediatric CNS tumors. Springer, Switzerland

Hovestadt V, Ayrault O, Swartling FJ, Robinson GW, Pfister SM, Northcott PA (2020) Medulloblastomics revisited: biological and clinical insights from thousands of patients. Nat Rev Cancer 20:42–56. https://doi.org/10.1038/s41568-019-0223-8CrossRefPubMed

Joshi P, Katsushima K, Zhou R, Meoded A, Stapleton S, Jallo G, Raabe E, Eberhart CG, Perera RJ (2019) The therapeutic and diagnostic potential of regulatory noncoding RNAs in medulloblastoma. Neurooncol Adv 1:023. https://doi.org/10.1093/noajnl/vdz023CrossRef

Kebudi R, Cakir FB, Agaoglu FY, Gorgun O, Ayan I, Darendeliler E (2013) Pediatric diffuse intrinsic pontine glioma patients from a single center. Childs Nerv Syst 29:583–588. https://doi.org/10.1007/s00381-012-1986-3CrossRefPubMed

Welby JP, Kaptzan T, Wohl A, Peterson TE, Raghunathan A, Brown DA, Gupta SK, Zhang L, Daniels DJ (2019) Current murine models and new developments in H3K27M diffuse midline gliomas. Front Oncol 9:92. https://doi.org/10.3389/fonc.2019.00092CrossRefPubMedPubMedCentral

Esteller M (2011) Non-coding RNAs in human disease. Nat Rev Genet 12:861–874. https://doi.org/10.1038/nrg3074CrossRefPubMed

Godlewski J, Krichevsky AM, Johnson MD, Chiocca EA, Bronisz A (2015) Belonging to a network–microRNAs, extracellular vesicles, and the glioblastoma microenvironment. Neuro Oncol 17:652–662. https://doi.org/10.1093/neuonc/nou292CrossRefPubMed

Nolte-’t Hoen EN, Buermans HP, Waasdorp M, Stoorvogel W, Wauben MH, ’t Hoen PA (2012) Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Res 40:9272–9285. https://doi.org/10.1093/nar/gks658CrossRefPubMedPubMedCentral

10.

Li CC, Eaton SA, Young PE, Lee M, Shuttleworth R, Humphreys DT, Grau GE, Combes V, Bebawy M, Gong J, Brammah S, Buckland ME, Suter CM (2013) Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells. RNA Biol 10:1333–1344. https://doi.org/10.4161/rna.25281CrossRefPubMedPubMedCentral

11.

Wei Z, Batagov AO, Schinelli S, Wang J, Wang Y, El Fatimy R, Rabinovsky R, Balaj L, Chen CC, Hochberg F, Carter B, Breakefield XO, Krichevsky AM (2017) Coding and noncoding landscape of extracellular RNA released by human glioma stem cells. Nat Commun 8:1145. https://doi.org/10.1038/s41467-017-01196-xCrossRefPubMedPubMedCentral

12.

Cambier L, de Couto G, Ibrahim A, Echavez AK, Valle J, Liu W, Kreke M, Smith RR, Marbán L, Marbán E (2017) Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion. EMBO Mol Med 9:337–352. https://doi.org/10.15252/emmm.201606924CrossRefPubMedPubMedCentral

13.

Epple LM, Griffiths SG, Dechkovskaia AM, Dusto NL, White J, Ouellette RJ, Anchordoquy TJ, Bemis LT, Graner MW (2012) Medulloblastoma exosome proteomics yield functional roles for extracellular vesicles. PLoS One 7:e42064. https://doi.org/10.1371/journal.pone.0042064CrossRefPubMedPubMedCentral

14.

Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, Bigner DD (2009) Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 23:1541–1557. https://doi.org/10.1096/fj.08-122184CrossRefPubMedPubMedCentral

15.

Bisaro B, Mandili G, Poli A, Piolatto A, Papa V, Novelli F, Cenacchi G, Forni M, Zanini C (2015) Proteomic analysis of extracellular vesicles from medullospheres reveals a role for iron in the cancer progression of medulloblastoma. Mol Cell Ther 3:8. https://doi.org/10.1186/s40591-015-0045-3CrossRefPubMedPubMedCentral

16.

Himes BT, Peterson TE, de Mooij T, Garcia LMC, Jung MY, Uhm S, Yan D, Tyson J, Jin-Lee HJ, Parney D, Abukhadra Y, Gustafson MP, Dietz AB, Johnson AJ, Dong H, Maus RL, Markovic S, Lucien F, Parney IF (2020) The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction. Neuro Oncol 22:967–978. https://doi.org/10.1093/neuonc/noaa029CrossRefPubMedPubMedCentral

17.

Cumba-Garcia LM, Peterson TE, Cepeda MA, Johnson AJ, Parney IF (2019) Isolation and analysis of plasma-derived exosomes in patients with glioma. Front Oncol 9:1–9CrossRef

18.

de Mooij T, Peterson TE, Evans J, McCutcheon B, Parney IF (2020) Short non-coding RNA sequencing of glioblastoma extracellular vesicles. J Neurooncol 146:253–263. https://doi.org/10.1007/s11060-019-03384-9CrossRefPubMed

19.

Jang JS, Simon VA, Feddersen RM, Rakhshan F, Schultz DA, Zschunke MA, Lingle WL, Kolbert CP, Jen J (2011) Quantitative miRNA expression analysis using fluidigm microfluidics dynamic arrays. BMC Genomics 12:144. https://doi.org/10.1186/1471-2164-12-144CrossRefPubMedPubMedCentral

20.

Fujita Y, Yoshioka Y, Ochiya T (2016) Extracellular vesicle transfer of cancer pathogenic components. Cancer Sci 107:385–390. https://doi.org/10.1111/cas.12896CrossRefPubMedPubMedCentral

21.

Ferretti E, De Smaele E, Po A, Di Marcotullio L, Tosi E, Espinola MS, Di Rocco C, Riccardi R, Giangaspero F, Farcomeni A, Nofroni I, Laneve P, Gioia U, Caffarelli E, Bozzoni I, Screpanti I, Gulino A (2009) MicroRNA profiling in human medulloblastoma. Int J Cancer 124:568–577. https://doi.org/10.1002/ijc.23948CrossRefPubMed

22.

Genovesi LA, Carter KW, Gottardo NG, Giles KM, Dallas PB (2011) Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells. PLoS One 6:e23935. https://doi.org/10.1371/journal.pone.0023935CrossRefPubMedPubMedCentral

23.

Dai J, Li Q, Bing Z, Zhang Y, Niu L, Yin H, Yuan G, Pan Y (2017) Comprehensive analysis of a microRNA expression profile in pediatric medulloblastoma. Mol Med Rep 15:4109–4115. https://doi.org/10.3892/mmr.2017.6490CrossRefPubMedPubMedCentral

24.

Shalaby T, Fiaschetti G, Baulande S, Gerber N, Baumgartner M, Grotzer M (2015) Detection and quantification of extracellular microRNAs in medulloblastom. J Cancer Metastasis Treat 1:67–75CrossRef

25.

Wang X, Holgado BL, Ramaswamy V, Mack S, Zayne K, Remke M, Wu X, Garzia L, Daniels C, Kenney AM, Taylor MD (2018) miR miR on the wall, who’s the most malignant medulloblastoma miR of them all? Neuro Oncol 20:313–323. https://doi.org/10.1093/neuonc/nox106CrossRefPubMed

26.

Liu J, Lu KH, Liu ZL, Sun M, De W, Wang ZX (2012) MicroRNA-100 is a potential molecular marker of non-small cell lung cancer and functions as a tumor suppressor by targeting polo-like kinase 1. BMC Cancer 12:519. https://doi.org/10.1186/1471-2407-12-519CrossRefPubMedPubMedCentral

27.

Haderk F, Schulz R, Iskar M, Cid LL, Worst T, Willmund KV, Schulz A, Warnken U, Seiler J, Benner A, Nessling M, Zenz T, Göbel M, Dürig J, Diederichs S, Paggetti J, Moussay E, Stilgenbauer S, Zapatka M, Lichter P, Seiffert M (2017) Tumor-derived exosomes modulate PD-L1 expression in monocytes. Sci Immunol. https://doi.org/10.1126/sciimmunol.aah5509CrossRefPubMed

28.

Schulte JH, Marschall T, Martin M, Rosenstiel P, Mestdagh P, Schlierf S, Thor T, Vandesompele J, Eggert A, Schreiber S, Rahmann S, Schramm A (2010) Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma. Nucleic Acids Res 38:5919–5928. https://doi.org/10.1093/nar/gkq342CrossRefPubMedPubMedCentral

29.

Luan W, Qian Y, Ni X, Bu X, Xia Y, Wang J, Ruan H, Ma S, Xu B (2017) miR-204-5p acts as a tumor suppressor by targeting matrix metalloproteinases-9 and B-cell lymphoma-2 in malignant melanoma. Onco Targets Ther 10:1237–1246. https://doi.org/10.2147/OTT.S128819CrossRefPubMedPubMedCentral

30.

Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, Bjerke L, Clarke M, Vinci M, Nandhabalan M, Temelso S, Popov S, Molinari V, Raman P, Waanders AJ, Han HJ, Gupta S, Marshall L, Zacharoulis S, Vaidya S, Mandeville HC, Bridges LR, Martin AJ, Al-Sarraj S, Chandler C, Ng HK, Li X, Mu K, Trabelsi S, Brahim DH, Kisljakov AN, Konovalov DM, Moore AS, Carcaboso AM, Sunol M, de Torres C, Cruz O, Mora J, Shats LI, Stavale JN, Bidinotto LT, Reis RM, Entz-Werle N, Farrell M, Cryan J, Crimmins D, Caird J, Pears J, Monje M, Debily MA, Castel D, Grill J, Hawkins C, Nikbakht H, Jabado N, Baker SJ, Pfister SM, Jones DTW, Fouladi M, von Bueren AO, Baudis M, Resnick A, Jones C (2017) Integrated molecular meta-analysis of 1000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32:520-537.e525. https://doi.org/10.1016/j.ccell.2017.08.017CrossRefPubMedPubMedCentral

31.

Miele E, Buttarelli FR, Arcella A, Begalli F, Garg N, Silvano M, Po A, Baldi C, Carissimo G, Antonelli M, Spinelli GP, Capalbo C, Donofrio V, Morra I, Nozza P, Gulino A, Giangaspero F, Ferretti E (2014) High-throughput microRNA profiling of pediatric high-grade gliomas. Neuro-oncol 16:228–240. https://doi.org/10.1093/neuonc/not215CrossRefPubMed

32.

Birks DK, Barton VN, Donson AM, Handler MH, Vibhakar R, Foreman NK (2011) Survey of MicroRNA expression in pediatric brain tumors. Pediatr Blood Cancer 56:211–216. https://doi.org/10.1002/pbc.22723CrossRefPubMed

33.

Tűzesi Á, Kling T, Wenger A, Lunavat TR, Jang SC, Rydenhag B, Lötvall J, Pollard SM, Danielsson A, Carén H (2017) Pediatric brain tumor cells release exosomes with a miRNA repertoire that differs from exosomes secreted by normal cells. Oncotarget 8:90164–90175. https://doi.org/10.18632/oncotarget.21621CrossRefPubMedPubMedCentral

34.

Hou BH, Jian ZX, Cui P, Li SJ, Tian RQ, Ou JR (2015) miR-216a may inhibit pancreatic tumor growth by targeting JAK2. FEBS Lett 589:2224–2232. https://doi.org/10.1016/j.febslet.2015.06.036CrossRefPubMed

35.

Fernandez-L A, Squatrito M, Northcott P, Awan A, Holland EC, Taylor MD, Nahlé Z, Kenney AM (2012) Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene 31:1923–1937. https://doi.org/10.1038/onc.2011.379CrossRefPubMed

36.

Dey A, Robitaille M, Remke M, Maier C, Malhotra A, Gregorieff A, Wrana JL, Taylor MD, Angers S, Kenney AM (2016) YB-1 is elevated in medulloblastoma and drives proliferation in sonic hedgehog-dependent cerebellar granule neuron progenitor cells and medulloblastoma cells. Oncogene 35:4256–4268. https://doi.org/10.1038/onc.2015.491CrossRefPubMedPubMedCentral

37.

Kowalski MP, Krude T (2015) Functional roles of non-coding Y RNAs. Int J Biochem Cell Biol 66:20–29. https://doi.org/10.1016/j.biocel.2015.07.003CrossRefPubMedPubMedCentral

38.

Pomytkin I, Costa-Nunes JP, Kasatkin V, Veniaminova E, Demchenko A, Lyundup A, Lesch KP, Ponomarev ED, Strekalova T (2018) Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment. CNS Neurosci Ther. https://doi.org/10.1111/cns.12866CrossRefPubMedPubMedCentral

39.

Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV, Mathivanan S, Quesenberry P, Sahoo S, Tahara H, Wauben MH, Witwer KW, Théry C (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the international society for extracellular vesicles. J Extracell Vesicles 3:26913. https://doi.org/10.3402/jev.v3.26913CrossRefPubMed

Titel: Pediatric brain tumor cell lines exhibit miRNA-depleted, Y RNA-enriched extracellular vesicles
verfasst von: Setty M. Magaña
Timothy E. Peterson
Jared E. Evans
Paul A. Decker
Vernadette Simon
Jeanette E. Eckel-Passow
David J. Daniels
Ian F. Parney
Publikationsdatum: 05.01.2022
Verlag: Springer US
Erschienen in: Journal of Neuro-Oncology / Ausgabe 2/2022
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-021-03914-4

Long-term outcomes of stereotactic radiosurgery for skull base tumors involving the cavernous sinus

Clinical Study

The integrated multiomic diagnosis of sporadic meningiomas: a review of its clinical implications

Open Access
Topic Review

Correction to: The integrated multiomic diagnosis of sporadic meningiomas: a review of its clinical implications

Open Access
Correction

Elevated baseline C-reactive protein levels predict poor progression-free survival in sporadic vestibular schwannoma

Open Access
Clinical Study

Stereotactic radiosurgery for vestibular schwannomas in neurofibromatosis type 2 patients: a systematic review and meta-analysis

Clinical Study

WDR34 affects PI3K/Akt and Wnt/β-catenin pathways to regulates malignant biological behaviors of glioma cells

Laboratory Investigation

Kompaktes Leitlinien-Wissen Neurologie (Link öffnet in neuem Fenster)

Mit medbee Pocketcards schnell und sicher entscheiden.
Leitlinien-Wissen kostenlos und immer griffbereit auf ihrem Desktop, Handy oder Tablet.

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Neuer FcRn-Blocker bremst Myasthenia gravis

24.01.2025
Myasthenia gravis
Nachrichten

Eine weitere Immuntherapie hat sich in einer Phase-3-Studie bei Myasthenia gravis bewährt: Mit dem Antikörper Nipocalimab gingen die Beschwerden bei Personen mit schlecht kontrollierter Erkrankung deutlich zurück.

Parkinsoninzidenz in Deutschland geht zurück

24.01.2025
Parkinson-Krankheit
Nachrichten

In Deutschland erkranken altersbezogen immer weniger Menschen an Morbus Parkinson: In den vergangenen 20 Jahren ist die Inzidenz um ein Fünftel gesunken. Das ergibt eine Analyse von AOK-Daten. Weshalb die Inzidenz zurückgeht, ist jedoch unklar.

„Wir wollen die Bedeutung von Gen- und Umwelteinflüssen besser verstehen“

Bipolare Störung
Interview

Eine Mutation in einem einzelnen Gen kann bei Mäusen eine Art Bipolarstörung auslösen. PD Dr. Jan Deussing vom Max-Planck-Institut für Psychiatrie in München sieht in solchen Tiermodellen eine Möglichkeit, den Ursachen der Erkrankung auf den Grund zu gehen.

Suizidassistenz erhöht Suizidzahlen: Aktuelle Ergebnisse der geplanten S3-Leitlinie

DGPPN 2024
Kongressbericht

Erstmals wird in Deutschland eine S3-Leitlinie zum Thema Suizidalität erarbeitet. Ziel ist es, die Versorgung in suizidalen Krisen durch einheitliche Standards zu verbessern. Erste Ergebnisse der bisherigen Leitlinienarbeit wurden auf dem DGPPN-Kongress vorgestellt.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Pediatric brain tumor cell lines exhibit miRNA-depleted, Y RNA-enriched extracellular vesicles