Skip to main content

Advertisement

Log in

Extracellular vesicle proteomes of two transmissible cancers of Tasmanian devils reveal tenascin-C as a serum-based differential diagnostic biomarker

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The iconic Tasmanian devil (Sarcophilus harrisii) is endangered due to the transmissible cancer Devil Facial Tumour Disease (DFTD), of which there are two genetically independent subtypes (DFT1 and DFT2). While DFT1 and DFT2 can be differentially diagnosed using tumour biopsies, there is an urgent need to develop less-invasive biomarkers that can detect DFTD and distinguish between subtypes. Extracellular vesicles (EVs), the nano-sized membrane-enclosed vesicles present in most biofluids, represent a valuable resource for biomarker discovery. Here, we characterized the proteome of EVs from cultured DFTD cells using data-independent acquisition–mass spectrometry and an in-house spectral library of > 1500 proteins. EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with focal adhesion functions. Furthermore, hallmark proteins of epithelial–mesenchymal transition were enriched in DFT2 EVs relative to DFT1 EVs. These findings were validated in EVs derived from serum samples, revealing that the mesenchymal marker tenascin-C was also enriched in EVs derived from the serum of devils infected with DFT2 relative to those infected with DFT1 and healthy controls. This first EV-based investigation of DFTD increases our understanding of the cancers’ EVs and their possible involvement in DFTD progression, such as metastasis. Finally, we demonstrated the potential of EVs to differentiate between DFT1 and DFT2, highlighting their potential use as less-invasive liquid biopsies for the Tasmanian devil.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The mass spectrometry raw proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [74] partner repository with the dataset identifier PXD020766 (cell lysate and EV samples); and PXD025579 (serum EV samples).

Code availability

Not applicable.

References

  1. Cunningham CX, Comte S, McCallum H, Hamilton DG, Hamede R, Storfer A, Hollings T, Ruiz-Aravena M, Kerlin DH, Brook BW, Hocking G, Jones ME (2021) Quantifying 25 years of disease-caused declines in tasmanian devil populations: host density drives spatial pathogen spread. Ecol Lett 24:958–969. https://doi.org/10.1111/ele.13703

    Article  PubMed  Google Scholar 

  2. Murchison EP, Tovar C, Hsu A, Bender HS, Kheradpour P, Rebbeck CA, Obendorf D, Conlan C, Bahlo M, Blizzard CA, Pyecroft S, Kreiss A, Kellis M, Stark A, Harkins TT, Marshall GJA, Woods GM, Hannon GJ, Papenfuss AT (2010) The Tasmanian devil transcriptome reveals Schwann cell origins of a clonally transmissible cancer. Science 327:84–87. https://doi.org/10.1126/science.1180616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hamede RK, McCallum H, Jones M (2013) Biting injuries and transmission of Tasmanian devil facial tumour disease. J Anim Ecol 82:182–190. https://doi.org/10.1111/j.1365-2656.2012.02025.x

    Article  PubMed  Google Scholar 

  4. Pye RJ, Pemberton D, Tovar C, Tubio JM, Dun KA, Fox S, Darby J, Hayes D, Knowles GW, Kreiss A, Siddle HV, Swift K, Lyons AB, Murchison EP, Woods GM (2016) A second transmissible cancer in tasmanian devils. Proc Natl Acad Sci USA 113:374–379. https://doi.org/10.1073/pnas.1519691113

    Article  CAS  PubMed  Google Scholar 

  5. Murchison EP, Schulz-Trieglaff OB, Ning Z, Alexandrov LB, Bauer MJ, Fu B, Hims M, Ding Z, Ivakhno S, Stewart C, Ng BL, Wong W, Aken B, White S, Alsop A, Becq J, Bignell GR, Cheetham RK, Cheng W, Connor TR, Cox AJ, Feng ZP, Gu Y, Grocock RJ, Harris SR, Khrebtukova I, Kingsbury Z, Kowarsky M, Kreiss A, Luo S, Marshall J, McBride DJ, Murray L, Pearse AM, Raine K, Rasolonjatovo I, Shaw R, Tedder P, Tregidgo C, Vilella AJ, Wedge DC, Woods GM, Gormley N, Humphray S, Schroth G, Smith G, Hall K, Searle SM, Carter NP, Papenfuss AT, Futreal PA, Campbell PJ, Yang F, Bentley DR, Evers DJ, Stratton MR (2012) Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer. Cell 148:780–791. https://doi.org/10.1016/j.cell.2011.11.065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. James S, Jennings G, Kwon YM, Stammnitz M, Fraik A, Storfer A, Comte S, Pemberton D, Fox S, Brown B, Pye R, Woods G, Lyons B, Hohenlohe PA, McCallum H, Siddle H, Thomas F, Ujvari B, Murchison EP, Jones M, Hamede R (2019) Tracing the rise of malignant cell lines: distribution, epidemiology and evolutionary interactions of two transmissible cancers in tasmanian devils. Evol Appl 12:1772–1780. https://doi.org/10.1111/eva.12831

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stammnitz MR, Coorens TH, Gori KC, Hayes D, Fu B, Wang J, Martin-Herranz DE, Alexandrov LB, Baez-Ortega A, Barthorpe S (2018) The origins and vulnerabilities of two transmissible cancers in tasmanian devils. Cancer Cell 33(607–619):e615. https://doi.org/10.1016/j.ccell.2018.03.013

    Article  CAS  Google Scholar 

  8. Ruiz-Aravena M, Jones ME, Carver S, Estay S, Espejo C, Storfer A, Hamede RK (2018) Sex bias in ability to cope with cancer: tasmanian devils and facial tumour disease. Proc Royal Soc 285:20182239. https://doi.org/10.1098/rspb.2018.2239

    Article  Google Scholar 

  9. McCallum H, Jones M, Hawkins C, Hamede R, Lachish S, Sinn DL, Beeton N, Lazenby B (2009) Transmission dynamics of Tasmanian devil facial tumor disease may lead to disease-induced extinction. Ecology 90:3379–3392. https://doi.org/10.1890/08-1763.1

    Article  PubMed  Google Scholar 

  10. Loh R, Bergfeld J, Hayes D, O’Hara A, Pyecroft S, Raidal S, Sharpe R (2006) The pathology of devil facial tumor disease (DFTD) in Tasmanian Devils (Sarcophilus harrisii). Vet Pathol 43:890–895. https://doi.org/10.1354/vp.43-6-890

    Article  CAS  PubMed  Google Scholar 

  11. Siddle HV, Kreiss A, Tovar C, Yuen CK, Cheng Y, Belov K, Swift K, Pearse AM, Hamede R, Jones ME, Skjodt K, Woods GM, Kaufman J (2013) Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer. Proc Natl Acad Sci USA 110:5103–5108. https://doi.org/10.1073/pnas.1219920110

    Article  PubMed  PubMed Central  Google Scholar 

  12. Caldwell A, Coleby R, Tovar C, Stammnitz MR, Kwon YM, Owen RS, Tringides M, Murchison EP, Skjodt K, Thomas GJ, Kaufman J, Elliott T, Woods GM, Siddle HV (2018) The newly-arisen devil facial tumour disease 2 (DFT2) reveals a mechanism for the emergence of a contagious cancer. Elife 7:e35314. https://doi.org/10.7554/eLife.35314

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hamede R, Lachish S, Belov K, Woods G, Kreiss A, Pearse AM, Lazenby B, Jones M, Mccallum H (2012) Reduced effect of tasmanian devil facial tumor disease at the disease front. Conserv Biol 26:124–134. https://doi.org/10.1111/j.1523-1739.2011.01747.x

    Article  PubMed  Google Scholar 

  14. Pyecroft SB, Pearse A-M, Loh R, Swift K, Belov K, Fox N, Noonan E, Hayes D, Hyatt A, Wang L (2007) Towards a case definition for devil facial tumour disease: what is it? EcoHealth 4:346. https://doi.org/10.1007/s10393-007-0126-0

    Article  Google Scholar 

  15. Tovar C, Obendorf D, Murchison EP, Papenfuss AT, Kreiss A, Woods GM (2011) Tumor-specific diagnostic marker for transmissible facial tumors of Tasmanian devils: immunohistochemistry studies. Vet Pathol 48:1195–1203. https://doi.org/10.1177/0300985811400447

    Article  CAS  PubMed  Google Scholar 

  16. Kwon YM, Stammnitz MR, Wang J, Swift K, Knowles GW, Pye RJ, Kreiss A, Peck S, Fox S, Pemberton D, Jones ME, Hamede R, Murchison EP (2018) Tasman-PCR: a genetic diagnostic assay for Tasmanian devil facial tumour diseases. R Soc Open Sci 5:180870. https://doi.org/10.1098/rsos.180870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hogg C, Fox S, Pemberton D, Belov K (2019) Chapter 3: Pathology and diagnostics of DFTD and other devil diseases. In: saving the Tasmanian devil: recovery through science-based management. CSIRO Publishing

    Google Scholar 

  18. Zaborowski MP, Balaj L, Breakefield XO, Lai CP (2015) Extracellular vesicles: composition, biological relevance, and methods of study. Bioscience 65:783–797. https://doi.org/10.1093/biosci/biv084

    Article  PubMed  PubMed Central  Google Scholar 

  19. Stahl PD, Raposo G (2019) Extracellular vesicles: exosomes and microvesicles, integrators of homeostasis. Physiology (Bethesda) 34:169–177. https://doi.org/10.1152/physiol.00045.2018

    Article  CAS  Google Scholar 

  20. Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579. https://doi.org/10.1038/nri855

    Article  CAS  PubMed  Google Scholar 

  21. Vlassov AV, Magdaleno S, Setterquist R, Conrad R (2012) Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Bba-Gen Subjects 1820:940–948. https://doi.org/10.1016/j.bbagen.2012.03.017

    Article  CAS  Google Scholar 

  22. Yang M, Wu SY (2018) The advances and challenges in utilizing exosomes for delivering cancer therapeutics. Front Pharmacol 9:735. https://doi.org/10.3389/fphar.2018.00735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheng L, Sharples RA, Scicluna BJ, Hill AF (2014) Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles 3:23743. https://doi.org/10.3402/jev.v3.23743

    Article  Google Scholar 

  24. Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK (2019) Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer 18:75. https://doi.org/10.1186/s12943-019-0991-5

    Article  PubMed  PubMed Central  Google Scholar 

  25. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar CM, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan JD, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang YB, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883. https://doi.org/10.1038/nm.2753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D (2016) Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30:836–848. https://doi.org/10.1016/j.ccell.2016.10.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic MM, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335. https://doi.org/10.1038/nature15756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Adem B, Vieira PF, Melo SA (2020) Decoding the biology of exosomes in metastasis. Trends Cancer 6:20–30. https://doi.org/10.1016/j.trecan.2019.11.007

    Article  CAS  PubMed  Google Scholar 

  29. Willms E, Cabanas C, Mager I, Wood MJA, Vader P (2018) Extracellular vesicle heterogeneity: subpopulations, isolation techniques, and diverse functions in cancer progression. Front Immunol 9:738. https://doi.org/10.3389/fimmu.2018.00738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331:1559–1564. https://doi.org/10.1126/science.1203543

    Article  CAS  PubMed  Google Scholar 

  31. LeBleu VS, Kalluri R (2020) Exosomes as a multicomponent biomarker platform in cancer. Trends Cancer 6:767–774. https://doi.org/10.1016/j.trecan.2020.03.007

    Article  CAS  PubMed  Google Scholar 

  32. Théry C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 30:332231–332229. https://doi.org/10.1002/0471143030.cb0322s30

    Article  Google Scholar 

  33. Abramowicz A, Marczak L, Wojakowska A, Zapotoczny S, Whiteside TL, Widlak P, Pietrowska M (2018) Harmonization of exosome isolation from culture supernatants for optimized proteomics analysis. PLoS ONE 13:e0205496. https://doi.org/10.1371/journal.pone.0205496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hughes CS, Moggridge S, Muller T, Sorensen PH, Morin GB, Krijgsveld J (2019) Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. Nat Protoc 14:68–85. https://doi.org/10.1038/s41596-018-0082-x

    Article  CAS  PubMed  Google Scholar 

  35. R Core Team (2020) R: a language and environment for statistical computing. R Foundation for Statistical Computing

    Google Scholar 

  36. Pathan M, Fonseka P, Chitti SV, Kang T, Sanwlani R, Van Deun J, Hendrix A, Mathivanan S (2019) Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res 47:D516–D519. https://doi.org/10.1093/nar/gky1029

    Article  CAS  PubMed  Google Scholar 

  37. Keerthikumar S, Chisanga D, Ariyaratne D, Al SH, Anand S, Zhao K, Samuel M, Pathan M, Jois M, Chilamkurti N, Gangoda L, Mathivanan S (2016) ExoCarta: a web-based compendium of exosomal cargo. J Mol Biol 428:688–692. https://doi.org/10.1016/j.jmb.2015.09.019

    Article  CAS  PubMed  Google Scholar 

  38. Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57. https://doi.org/10.1038/nprot.2008.211

    Article  CAS  Google Scholar 

  39. Huang DW, Sherman BT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37:1–13. https://doi.org/10.1093/nar/gkn923

    Article  CAS  Google Scholar 

  40. Glaab E, Baudot A, Krasnogor N, Schneider R, Valencia A (2012) EnrichNet: network-based gene set enrichment analysis. Bioinformatics 28:i451–i457. https://doi.org/10.1093/bioinformatics/bts389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E (2003) PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273. https://doi.org/10.1038/ng1180

    Article  CAS  PubMed  Google Scholar 

  43. Reimand J, Isserlin R, Voisin V, Kucera M, Tannus-Lopes C, Rostamianfar A, Wadi L, Meyer M, Wong J, Xu CJ, Merico D, Bader GD (2019) Pathway enrichment analysis and visualization of omics data using g:Profiler, GSEA, cytoscape and enrichmentmap. Nat Protoc 14:482–517. https://doi.org/10.1038/s41596-018-0103-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593. https://doi.org/10.1038/nri2567

    Article  CAS  PubMed  Google Scholar 

  45. Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Zavec AB, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borras FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MA, Brigstock DR, Brisson A, Broekman MLD, Bromberg JF, Bryl-Gorecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzas EI, Byrd JB, Camussi G, Carter DRF, Caruso S, Chamley LW, Chang YT, Chen CC, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FAW, Coyle B, Crescitelli R, Criado MF, D'Souza-Schorey C, Das S, Chaudhuri AD, Candia P, De Santana EF, De Wever O, del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Rubio APD, Dominici M, Dourado MR, Driedonks TAP, Duarte FV, Duncan HM, Eichenberger RM, Ekstrom K, Andaloussi SEL, Elie-Caille C, Erdbrugger U, Falcon-Perez JM, Fatima F, Fish JE, Flores-Bellver M, Forsonits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gamez-Valero A, Gardiner C, Gartner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DCI, Gorgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu GK, Huang YY, Huber V, Hunt S, Ibrahim AGE, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang LZ, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano S, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ, Kornek M, Kosanovic MM, Kovacs AF, Kramer-Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lasser C, Laurent LC, Lavieu G, Lazaro-Ibanez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, Li ITS., Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Line A, Linnemannstons K, Llorente A, Lombard CA, Lorenowicz MJ, Lorincz AM, Lotvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, Maas SLN, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens-Uzunova ES, Martin-Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, McGinnis LK, McVey MJ, Meckes DG, Meehan KL, Mertens I, Minciacchi VR, Moller A, Jorgensen MM, Morales-Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte-'t Hoen ENM, Noren Hooten N, O'Driscoll L, O'Grady T, O'Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Ostegaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BCH, Pink RC, Pisetsky DS, von Strandmann EP, Polakovicova I, Poon IKH, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev-Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KMA, Rughetti A, Russell AE, Saa P, Sahoo S, Salas-Huenuleo E, Sanchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schoyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, Siljander PRM, Silva AM, Skowronek A, Snyder OL, Soares RP, Sodar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BWM, van der Grein SG, Van Deun J, van Herwijnen MJC, Van Keuren-Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJ, Veit TD., Vella LJ, Velot E, Verweij FJ, Vestad B, Vinas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MHM, Weaver A, Webber JP, Weber V., Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan XM., Yanez-Mo M, Yin H, Yuana Y, Zappulli V, Zarubova J, Zekas V, Zhang JY, Zhao ZZ, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK (2018) Minimal information for studies of extracellular vesicles (MISEV): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7:1535750. https://doi.org/10.1080/20013078.2018.1535750

  46. Patchett AL, Coorens THH, Darby J, Wilson R, McKay MJ, Kamath KS, Rubin A, Wakefield M, McIntosh L, Mangiola S, Pye RJ, Flies AS, Corcoran LM, Lyons AB, Woods GM, Murchison EP, Papenfuss AT, Tovar C (2020) Two of a kind: transmissible Schwann cell cancers in the endangered Tasmanian devil (Sarcophilus harrisii). Cell Mol Life Sci 77:1847–1858. https://doi.org/10.1007/s00018-019-03259-2

    Article  CAS  PubMed  Google Scholar 

  47. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, Dingli F, Loew D, Tkach M, Thery C (2016) Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A 113:E968-977. https://doi.org/10.1073/pnas.1521230113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. D’Alessio S, Thorgeirsdottir S, Kraev I, Skirnisson K, Lange S (2021) Post-translational protein deimination signatures in plasma and plasma evs of reindeer (Rangifer tarandus). Biology 10:222. https://doi.org/10.3390/biology10030222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Magnadottir B, Uysal-Onganer P, Kraev I, Svansson V, Hayes P, Lange S (2020) Deiminated proteins and extracellular vesicles - Novel serum biomarkers in whales and orca. Comp Biochem Physiol Part D Genomics Proteomics 34:100676. https://doi.org/10.1016/j.cbd.2020.100676

    Article  CAS  PubMed  Google Scholar 

  50. Phillips RA, Kraev I, Lange S (2020) Protein deimination and extracellular vesicle profiles in antarctic seabirds. Biology 9:15. https://doi.org/10.3390/biology9010015

    Article  CAS  PubMed Central  Google Scholar 

  51. Maziveyi M, Alahari SK (2017) Cell matrix adhesions in cancer. The proteins that form the glue. Oncotarget 8:48471–48487. https://doi.org/10.18632/oncotarget.17265

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ghoroghi S, Mary B, Larnicol A, Asokan N, Klein A, Osmani N, Busnelli I, Delalande F, Paul N, Halary S, Gros F, Fouillen L, Haeberle AM, Royer C, Spiegelhalter C, Andre-Gregoire G, Mittelheisser V, Detappe A, Murphy K, Timpson P, Carapito R, Blot-Chabaud M, Gavard J, Carapito C, Vitale N, Lefebvre O, Goetz JG, Hyenne V (2021) Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes. Elife 10:e61539. https://doi.org/10.7554/eLife.61539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428. https://doi.org/10.1172/JCI39104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768. https://doi.org/10.1038/nrc2499

    Article  CAS  PubMed  Google Scholar 

  55. Ksiazkiewicz M, Markiewicz A, Zaczek AJ (2012) Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology 79:195–208. https://doi.org/10.1159/000337106

    Article  PubMed  Google Scholar 

  56. Wang Y, Zhou BP (2013) Epithelial-mesenchymal transition—a hallmark of breast cancer metastasis. Cancer Hall 1:38–49. https://doi.org/10.1166/ch.2013.1004

    Article  Google Scholar 

  57. Syn N, Wang L, Sethi G, Thiery J-P, Goh B-C (2016) Exosome-mediated metastasis: from epithelial–mesenchymal transition to escape from immunosurveillance. Trends Pharmacol Sci Trends Pharmacol Sci 37:606–617. https://doi.org/10.1016/j.tips.2016.04.006

    Article  CAS  PubMed  Google Scholar 

  58. Jessen KR, Mirsky R (2019) The success and failure of the schwann cell response to nerve injury. Front Cell Neurosci 13:33. https://doi.org/10.3389/fncel.2019.00033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Midwood KS, Chiquet M, Tucker RP, Orend G (2016) Tenascin-C at a glance. J Cell Sci 129:4321–4327. https://doi.org/10.1242/jcs.190546

    Article  CAS  PubMed  Google Scholar 

  60. Angel I, Kerman OP, Rousso-Noori L, Friedmann-Morvinski D (2020) Tenascin C promotes cancer cell plasticity in mesenchymal glioblastoma. Oncogene 39:6990–7004. https://doi.org/10.1038/s41388-020-01506-6

    Article  CAS  PubMed  Google Scholar 

  61. Takahashi Y, Sawada G, Kurashige J, Matsumura T, Uchi R, Ueo H, Ishibashi M, Takano Y, Akiyoshi S, Iwaya T (2013) Tumor-derived tenascin-C promotes the epithelial-mesenchymal transition in colorectal cancer cells. Anticancer Res 33:1927–1934. https://doi.org/10.3892/ol.2021.12831

    Article  CAS  PubMed  Google Scholar 

  62. Nagaharu K, Zhang X, Yoshida T, Katoh D, Hanamura N, Kozuka Y, Ogawa T, Shiraishi T, Imanaka-Yoshida K (2011) Tenascin C induces epithelial-mesenchymal transition–like change accompanied by SRC activation and focal adhesion kinase phosphorylation in human breast cancer cells. Am J Pathol 178:754–763. https://doi.org/10.1016/j.ajpath.2010.10.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yoshida T, Akatsuka T, Imanaka-Yoshida K (2015) Tenascin-C and integrins in cancer. Cell Adh Migr 9:96–104. https://doi.org/10.1080/19336918.2015.1008332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hoshino A, Kim HS, Bojmar L, Gyan KE, Cioffi M, Hernandez J, Zambirinis CP, Rodrigues G, Molina H, Heissel S, Mark MT, Steiner L, Benito-Martin A, Lucotti S, Di Giannatale A, Offer K, Nakajima M, Williams C, Nogues L, Pelissier Vatter FA, Hashimoto A, Davies AE, Freitas D, Kenific CM, Ararso Y, Buehring W, Lauritzen P, Ogitani Y, Sugiura K, Takahashi N, Aleckovic M, Bailey KA, Jolissant JS, Wang H, Harris A, Schaeffer LM, Garcia-Santos G, Posner Z, Balachandran VP, Khakoo Y, Raju GP, Scherz A, Sagi I, Scherz-Shouval R, Yarden Y, Oren M, Malladi M, Petriccione M, De Braganca KC, Donzelli M, Fischer C, Vitolano S, Wright GP, Ganshaw L, Marrano M, Ahmed A, DeStefano J, Danzer E, Roehrl M HA, Lacayo NJ, Vincent TC, Weiser MR, Brady MS, Meyers PA, Wexler LH, Ambati SR, Chou AJ, Slotkin EK, Modak S, Roberts SS, Basu EM, Diolaiti D, Krantz BA, Cardoso F, Simpson AL, Berger M, Rudin CM, Simeone DM, Jain M, Ghajar CM, Batra SK, Stanger BZ, Bui J, Brown KA, Rajasekhar VK, Healey JH, de Sousa M, Kramer K, Sheth S, Baisch J, Pascual V, Heaton TE, La Quaglia MP, Pisapia DJ, Schwartz R, Zhang H, Liu Y, Shukla A, Blavier L, DeClerck YA, LaBarge M, Bissell MJ, Caffrey TC, Grandgenett PM, Hollingsworth MA, Bromberg J, Costa-Silva B, Peinado H, Kang Y, Garcia BA, O'Reilly EM, Kelsen D, Trippett TM, Jones DR, Matei IR, Jarnagin WR, Lyden D (2020) Extracellular vesicle and particle biomarkers define multiple human cancers. Cell 182:1044-1061e1018. https://doi.org/10.1016/j.cell.2020.07.009

  65. Wan Z, Gao X, Dong Y, Zhao Y, Chen X, Yang G, Liu L (2018) Exosome-mediated cell-cell communication in tumor progression. Am J Cancer Res 8:1661–1673. https://doi.org/10.1002/jev2.12125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Samuelson I, Vidal-Puig AJ (2018) Fed-EXosome: Extracellular vesicles and cell–cell communication in metabolic regulation. Essays Biochem 62:165–175. https://doi.org/10.1042/EBC20170087

    Article  PubMed  Google Scholar 

  67. Maia J, Caja S, Strano MMC, Couto N, Costa-Silva B (2018) Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol 6:18. https://doi.org/10.3389/fcell.2018.00018

    Article  PubMed  PubMed Central  Google Scholar 

  68. Redzic JS, Kendrick AA, Bahmed K, Dahl KD, Pearson CG, Robinson WA, Robinson SE, Graner MW, Eisenmesser EZ (2013) Extracellular vesicles secreted from cancer cell lines stimulate secretion of MMP-9, IL-6, TGF-β1 and EMMPRIN. PLoS ONE 8:e71225. https://doi.org/10.1371/journal.pone.0071225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Xu Y, Zhang Y, Wang L, Zhao R, Qiao Y, Han D, Sun Q, Dong N, Liu Y, Wu D, Zhang X, Huang N, Ma N, Zhao W, Liu Y, Gao X (2017) miR-200a targets Gelsolin: a novel mechanism regulating secretion of microvesicles in hepatocellular carcinoma cells. Oncol Rep 37:2711–2719. https://doi.org/10.3892/or.2017.5506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wu KR, Xing F, Wu SY, Watabe K (2017) Extracellular vesicles as emerging targets in cancer: recent development from bench to bedside. Bba-Rev Cancer 1868:538–563. https://doi.org/10.1016/j.bbcan.2017.10.001

    Article  CAS  Google Scholar 

  71. Hasselmann DO, Rappl G, Tilgen W, Reinhold U (2001) Extracellular tyrosinase mRNA within apoptotic bodies is protected from degradation in human serum. Clin Chem 47:1488–1489. https://doi.org/10.1093/clinchem/47.8.1488

    Article  CAS  PubMed  Google Scholar 

  72. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, Hristov M, Koppel T, Jahantigh MN, Lutgens E, Wang S, Olson EN, Schober A, Weber C (2009) Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2:81. https://doi.org/10.1126/scisignal.2000610

    Article  Google Scholar 

  73. Abu-Helil B, van der Weyden L (2019) Metastasis in the wild: investigating metastasis in non-laboratory animals. Clin Exp Metastasis 36:15–28. https://doi.org/10.1007/s10585-019-09956-3

    Article  PubMed  PubMed Central  Google Scholar 

  74. Askenase PW (2021) Ancient evolutionary origin and properties of universally produced natural exosomes contribute to their therapeutic superiority compared to artificial nanoparticles. Int J Mol Sci 22:1429. https://doi.org/10.3390/ijms22031429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Perez-Riverol Y, Csordas A, Bai J, Bernal-Llinares M, Hewapathirana S, Kundu DJ, Inuganti A, Griss J, Mayer G, Eisenacher M, Perez E, Uszkoreit J, Pfeuffer J, Sachsenberg T, Yilmaz S, Tiwary S, Cox J, Audain E, Walzer M, Jarnuczak AF, Ternent T, Brazma A, Vizcaino JA (2019) The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res 47:D442–D450. https://doi.org/10.1093/nar/gky1106

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge all the members of the devil and wild immunology group for their advice and guidance. We would also like to thank Ginny Ralph for providing care of captive devils, the Bonorong Wildlife Sanctuary for providing access to Tasmanian devils and Dr Alexandre Kreiss for collecting the blood and to the Save the Tasmanian Devil Program for provision of samples. The authors would also like to acknowledge La Trobe University Bioimaging Platform for their support with TEM analysis.

Funding

This work was supported by the National Geographic explorer early career grant, Holsworth Wildlife Research Endowment grants, the University of Tasmania Foundation through funds raised by the Save the Tasmanian Devil Appeal. Proteomics infrastructure was funded by ARC LE180100059. Sample collection from wild devils was funded by US National Institutes of Health (NIH) grant R01-GM126563-01 and US National Science Foundation (NSF) grant DEB1316549 as part of the joint NIH-NSF-USDA Ecology and Evolution of Infectious Diseases program.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Camila Espejo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal procedures were performed under a Standard Operating Procedure approved by the General Manager, Natural and Cultural Heritage Division, Tasmanian Government Department of Primary Industries, Parks, Water and the Environment and under the auspices of the University of Tasmania Animal Ethics Committee (permit numbers: A0017550, A0013326, A0015835).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Espejo, C., Wilson, R., Willms, E. et al. Extracellular vesicle proteomes of two transmissible cancers of Tasmanian devils reveal tenascin-C as a serum-based differential diagnostic biomarker. Cell. Mol. Life Sci. 78, 7537–7555 (2021). https://doi.org/10.1007/s00018-021-03955-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-021-03955-y

Keywords

Navigation