Heterogeneity of Extracellular Vesicles and Particles: Molecular Voxels in the Blood Borne “Hologram” of Organ Function, Dysfunction and Cancer

Aalberts M, Stout TA, Stoorvogel W (2014) Prostasomes: extracellular vesicles from the prostate. Reproduction 147:R1-14. https://doi.org/10.1530/rep-13-0358 Adnani L, Kassouf J, Meehan B et al (2022a) Angiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells. Nat Commun 13:5494. https://doi.org/10.1038/s41467-022-33235-7 Adnani L, Spinelli C, Tawil N, Rak J (2022b) Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature. Semin Cancer Biol 87:196–213. https://doi.org/10.1016/j.semcancer.2022.11.003 Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7:834–846. https://doi.org/10.1038/nrc2256 Al-Hajj M, Wicha MS, Ito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988. https://doi.org/10.1073/pnas.0530291100 Al-Nedawi K, Meehan B, Micallef J et al (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10:619–624. https://doi.org/10.1038/ncb1725 Arraud N, Linares R, Tan S et al (2014) Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost 12:614–627. https://doi.org/10.1111/jth.12554 Bálint Š, Müller S, Fischer R et al (2020) Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells. Science 368:897–901. https://doi.org/10.1126/science.aay9207 Barault L, Amatu A, Bleeker FE et al (2015) Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer. Ann Oncol 26:1994–1999. https://doi.org/10.1093/annonc/mdv272 Barman B, Sung BH, Krystofiak E et al (2022) VAP-A and its binding partner CERT drive biogenesis of RNA-containing extracellular vesicles at ER membrane contact sites. Dev Cell 57:974-994.e8. https://doi.org/10.1016/j.devcel.2022.03.012 Bishop JM (1995) Cancer: the rise of the genetic paradigm. Genes Dev 9:1309–1315. https://doi.org/10.1101/gad.9.11.1309 Black WC, Welch HG (1993) Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med 328:1237–1243. https://doi.org/10.1056/NEJM199304293281706 Boccaccio C, Sabatino G, Medico E et al (2005) The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 434:396–400. https://doi.org/10.1038/nature03357 Bonavia R, Inda MM, Cavenee WK et al (2011) Heterogeneity maintenance in glioblastoma: a social network. Cancer Res 71:4055–4060. https://doi.org/10.1158/0008-5472.CAN-11-0153 Bordanaba-Florit G, Royo F, Kruglik SG et al (2021) Using single-vesicle technologies to unravel the heterogeneity of extracellular vesicles. Nat Protoc 16:3163–3185. https://doi.org/10.1038/s41596-021-00551-z Broekman ML, Maas SLN, Abels ER et al (2018) Multidimensional communication in the microenvirons of glioblastoma. Nat Rev Neurol 14:482–495. https://doi.org/10.1038/s41582-018-0025-8 Calabrese C, Poppleton H, Kocak M et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82. https://doi.org/10.1016/j.ccr.2006.11.020 Chennakrishnaiah S, Meehan B, D’Asti E et al (2018) Leukocytes as a reservoir of circulating oncogenic DNA and regulatory targets of tumor-derived extracellular vesicles. J Thromb Haemost 16:1800–1813. https://doi.org/10.1111/jth.14222 Chennakrishnaiah S, Tsering T, Gregory C et al (2020) Extracellular vesicles from genetically unstable, oncogene-driven cancer cells trigger micronuclei formation in endothelial cells. Sci Rep 10:8532. https://doi.org/10.1038/s41598-020-65640-7 Choi D, Lee TH, Spinelli C, Chennakrishnaiah S et al (2017) Extracellular vesicle communication pathways as regulatory targets of oncogenic transformation. Semin Cell Dev Biol 67:11–22. https://doi.org/10.1016/j.semcdb.2017.01.003 Choi D, Montermini L, Kim DK et al (2018) The impact of oncogenic EGFRvIII on the proteome of extracellular vesicles released from glioblastoma cells. Mol Cell Proteomics 17:1948–1964. https://doi.org/10.1074/mcp.RA118.000644 Choi D, Montermini L, Jeong H et al (2019) Mapping subpopulations of cancer cell-derived extracellular vesicles and particles by nano-flow cytometry. ACS Nano 13:10499–10511. https://doi.org/10.1021/acsnano.9b04480 Clos-Sansalvador M, Monguió-Tortajada M, Roura S et al (2022) Commonly used methods for extracellular vesicles’ enrichment: implications in downstream analyses and use. Eur J Cell Biol 101:151227. https://doi.org/10.1016/j.ejcb.2022.151227 Coumans FAW, Brisson AR, Buzas EI et al (2017) Methodological guidelines to study extracellular vesicles. Circ Res 120:1632–1648. https://doi.org/10.1161/circresaha.117.309417 Dameron KM, Volpert OV, Tainsky MA et al (1994) The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin. Cold Spring Harb Symp Quant Biol 59:483–489. https://doi.org/10.1101/sqb.1994.059.01.053 Di Vizio D, Kim J, Hager MH et al (2009) Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease. Cancer Res 69:5601–5609. https://doi.org/10.1158/0008-5472.CAN-08-3860 Dieudé M, Turgeon J, Karakeussian Rimbaud A et al (2020) Extracellular vesicles derived from injured vascular tissue promote the formation of tertiary lymphoid structures in vascular allografts. Am J Transplant 20:726–738. https://doi.org/10.1111/ajt.15707 Droste M, Tertel T, Jeruschke S et al (2021) Single extracellular vesicle analysis performed by imaging flow cytometry and nanoparticle tracking analysis evaluate the accuracy of urinary extracellular vesicle preparation techniques differently. Int J Mol Sci 22:12436. https://doi.org/10.3390/ijms222212436 Fabbiano F, Corsi J, Gurrieri E et al (2020) RNA packaging into extracellular vesicles: an orchestra of RNA-binding proteins? J Extracell Vesicles 10:e12043. https://doi.org/10.1002/jev2.12043 Fidler IJ (1973) Selection of successive cell lines for metastasis. Nature 242:148–149. https://doi.org/10.1038/newbio242148a0 Fiedorowicz A, Kozak-Sykała A, Bobak Ł et al (2019) Ceramides and sphingosine-1-phosphate as potential markers in diagnosis of ischaemic stroke. Neurol Neurochir Pol 53:484–491. https://doi.org/10.5603/PJNNS.a2019.0063 Garnier D, Magnus N, Lee TH et al (2012) Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor. J Biol Chem 287:43565–43572. https://doi.org/10.1074/jbc.M112.401760 Garnier D, Meehan B, Kislinger T et al (2018) Divergent evolution of temozolomide resistance in glioblastoma stem cells is reflected in extracellular vesicles and coupled with radiosensitization. Neuro Oncol 20:236–248. https://doi.org/10.1093/neuonc/nox142 Geddings JE, Mackman N (2013) Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 122:1873–1880. https://doi.org/10.1182/blood-2013-04-460139 Goveia J, Rohlenova K, Taverna F et al (2020) An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell 37:21-36.e13. https://doi.org/10.1016/j.ccell.2019.12.001 Graner MW, Alzate O, Dechkovskaia AM et al (2009) Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 23:1541–1557. https://doi.org/10.1096/fj.08-122184 Greco V, Hannus M, Eaton S (2001) Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106:633–645. https://doi.org/10.1016/s0092-8674(01)00484-6 Greening DW, Simpson RJ (2018) Understanding extracellular vesicle diversity–current status. Expert Rev Proteomics 15:887–910. https://doi.org/10.1080/14789450.2018.1537788 Greening DW, Xu R, Gopal SK et al (2016) Proteomic insights into extracellular vesicle biology–defining exosomes and shed microvesicles. Expert Rev Proteomics 14:69–95. https://doi.org/10.1080/14789450.2017.1260450 Gyorgy B, Szabo TG, Pasztoi M et al (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68:2667–2688. https://doi.org/10.1007/s00018-011-0689-3 Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013 Hanjani NA, Esmaelizad N, Zanganeh S et al (2022) Emerging role of exosomes as biomarkers in cancer treatment and diagnosis. Crit Rev Oncol Hematol 169:103565. https://doi.org/10.1016/j.critrevonc.2021.103565 Hendrix A, Westbroek W, Bracke M et al (2010) An ex(o)citing machinery for invasive tumor growth. Cancer Res 70:9533–9537. https://doi.org/10.1158/0008-5472.CAN-10-3248 Heppner GH (1983) Tumor subpopulation interactions in neoplasms. Bioch Biophys Acta 695:215–226. https://doi.org/10.1016/0304-419x(83)90012-4 Higginbotham JN, Zhang Q, Jeppesen DK et al (2016) Identification and characterization of EGF receptor in individual exosomes by fluorescence-activated vesicle sorting. J Extracell Vesicles 5:29254. https://doi.org/10.3402/jev.v5.29254 Hoshino A, Costa-Silva B, Shen TL et al (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335. https://doi.org/10.1038/nature15756 Hoshino A, Kim HS, Bojmar L et al (2020) Extracellular vesicle and particle biomarkers define multiple human cancers. Cell 182:1044-1061.e18. https://doi.org/10.1016/j.cell.2020.07.009 Hosseini II, Liu Z, Capaldi X et al (2021) Nanofluidics for simultaneous size and charge profiling of extracellular vesicles. Nano Lett 21:4895–4902. https://doi.org/10.1021/acs.nanolett.0c02558 Huang D, Liu J, Eldridge RC et al (2020) Lipidome signatures of metastasis in a transgenic mouse model of sonic hedgehog medulloblastoma. Anal Bioanal Chem 412:7017–7027. https://doi.org/10.1007/s00216-020-02837-9 Ignatiadis M, Sledge GW, Jeffrey SS (2021) Liquid biopsy enters the clinic–implementation issues and future challenges. Nat Rev Clin Oncol 18:297–312. https://doi.org/10.1038/s41571-020-00457-x Inda MM, Bonavia R, Mukasa A et al (2010) Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev 24:1731–1745. https://doi.org/10.1101/gad.1890510 Jalali M, Isaac Hosseini I, AbdelFatah T et al (2021) Plasmonic nanobowtiefluidic device for sensitive detection of glioma extracellular vesicles by Raman spectrometry. Lab Chip 21:855–866. https://doi.org/10.1039/d0lc00957a Jeppesen DK, Fenix AM, Franklin JL et al (2019) Reassessment of exosome composition. Cell 177:428-445.e18. https://doi.org/10.1016/j.cell.2019.02.029 Khorana AA, Mackman N, Falanga A et al (2022) Cancer-associated venous thromboembolism. Nat Rev Dis Primers 8:11. https://doi.org/10.1038/s41572-022-00336-y Kilinc S, Paisner R, Camarda R et al (2021) Oncogene-regulated release of extracellular vesicles. Dev Cell 56:1989-2006.e6. https://doi.org/10.1016/j.devcel.2021.05.014 Killingsworth B, Welsh JA, Jones JC (2021) EV translational horizons as viewed across the complex landscape of liquid biopsies. Front Cell Dev Biol 9:556837. https://doi.org/10.3389/fcell.2021.556837 Koch R, Demant M, Aung T et al (2014) Populational equilibrium through exosome-mediated Wnt signaling in tumor progression of diffuse large B-cell lymphoma. Blood 123:2189–2198. https://doi.org/10.1182/blood-2013-08-523886 Kowal J, Arras G, Colombo M et al (2016) Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA 113:E968–E977. https://doi.org/10.1073/pnas.1521230113 Kugeratski FG, Hodge K, Lilla S et al (2021) Quantitative proteomics identifies the core proteome of exosomes with syntenin-1 as the highest abundant protein and a putative universal biomarker. Nat Cell Biol 23:631–641. https://doi.org/10.1038/s41556-021-00693-y Lakkaraju A, Rodriguez-Boulan E (2008) Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol 18:199–209. https://doi.org/10.1016/j.tcb.2008.03.002 Lázaro-Ibáñez E, Faruqu FN, Saleh AF et al (2021) Selection of fluorescent, bioluminescent, and radioactive tracers to accurately reflect extracellular vesicle biodistribution in vivo. ACS Nano 15:3212–3227. https://doi.org/10.1021/acsnano.0c09873 Lee TH, Chennakrishnaiah S, Audemard E et al (2014) Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells. Biochem Biophys Res Commun 451:295–301. https://doi.org/10.1016/j.bbrc.2014.07.109 Leidal AM, Debnath J (2020) Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles. Methods 177:15–26. https://doi.org/10.1016/j.ymeth.2020.01.008 Li B, Antonyak MA, Zhang J et al (2012) RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells. Oncogene 31:4740–4749. https://doi.org/10.1038/onc.2011.636 Li M, Liao L, Tian W (2020) Extracellular vesicles derived from apoptotic cells: an essential link between death and regeneration. Front Cell Dev Biol 8:573511. https://doi.org/10.3389/fcell.2020.573511 Li Z, Seehawer M, Polyak K (2022) Untangling the web of intratumour heterogeneity. Nat Cell Biol 24:1192–1201. https://doi.org/10.1038/s41556-022-00969-x Liang Y, Lehrich BM, Zheng S et al (2021) Emerging methods in biomarker identification for extracellular vesicle-based liquid biopsy. J Extracell Vesicles 10:e12090. https://doi.org/10.1002/jev2.12090 Lu J, Ye X, Fan F et al (2013) Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23:171–185. https://doi.org/10.1016/j.ccr.2012.12.021 Lucero R, Zappulli V, Sammarco A et al (2020) Glioma-derived miRNA-containing extracellular vesicles induce angiogenesis by reprogramming brain endothelial cells. Cell Rep 30:2065-2074.e4. https://doi.org/10.1016/j.celrep.2020.01.073 Luck K, Kim DK, Lambourne L et al (2020) A reference map of the human binary protein interactome. Nature 580:402–408. https://doi.org/10.1038/s41586-020-2188-x Luxmi R, King SM (2022) Cilia-derived vesicles: an ancient route for intercellular communication. Semin Cell Dev Biol 129:82–92. https://doi.org/10.1016/j.semcdb.2022.03.014 Magnus N, Garnier D, Meehan B et al (2014) Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations. Proc Natl Acad Sci USA 111:3544–3549. https://doi.org/10.1073/pnas Margolis E, Brown G, Partin A et al (2022) Predicting high-grade prostate cancer at initial biopsy: clinical performance of the ExoDx (EPI) prostate intelliscore test in three independent prospective studies. Prostate Cancer Prostatic Dis 25:296–301. https://doi.org/10.1038/s41391-021-00456-8 Marki A, Ley K (2022) The expanding family of neutrophil-derived extracellular vesicles. Immunol Rev 312:52–60. https://doi.org/10.1111/imr.13103 Martincorena I, Roshan A, Gerstung M et al (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348:880–886. https://doi.org/10.1126/science.aaa6806 Mathieu M, Martin-Jaular L, Lavieu G et al (2019) Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 21:9–17. https://doi.org/10.1038/s41556-018-0250-9 Meehan B, Rak J, Di Vizio D (2016) Oncosomes - large and small: what are they, where they came from? J Extracell Vesicles 5:33109. https://doi.org/10.3402/jev.v5.33109 Mittal S, Chaudhary A, Chaudhary A, Kumar A (2020) Proniosomes: the effective and efficient drug-carrier system. Ther Deliv 11:125–137. https://doi.org/10.4155/tde-2019-0065 Montermini L, Meehan B, Garnier D et al (2015) Inhibition of oncogenic epidermal growth factor receptor kinase triggers release of exosome-like extracellular vesicles and impacts their phosphoprotein and DNA content. J Biol Chem 290:24534–24546. https://doi.org/10.1074/jbc.M115.679217 Mulcahy LA, Pink RC, Carter DR (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. https://doi.org/10.3402/jev.v3.24641 Muralidharan-Chari V, Clancy J, Plou C et al (2009) ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr Biol 19:1875–1885. https://doi.org/10.1016/j.cub.2009.09.059 Mutch SA, Kensel-Hammes P, Gadd JC et al (2011) Protein quantification at the single vesicle level reveals that a subset of synaptic vesicle proteins are trafficked with high precision. J Neurosci 31:1461–1470. https://doi.org/10.1523/jneurosci.3805-10.2011 Neftel C, Laffy J, Filbin MG et al (2019) An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 178:835-849.e21. https://doi.org/10.1016/j.cell.2019.06.024 Osswald M, Jung E, Sahm F et al (2015) Brain tumour cells interconnect to a functional and resistant network. Nature 528:93–98. https://doi.org/10.1038/nature16071 Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33:967–978. https://doi.org/10.1016/0092-8674(83)90040-5 Peinado H, Aleckovic M, Lavotshkin S et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:833–891. https://doi.org/10.1038/nm.2753 Pelosof LC, Gerber DE (2010) Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc 85:838–854. https://doi.org/10.4065/mcp.2010.0099 Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171. https://doi.org/10.1016/j.blre.2006.09.001 Puhm F, Afonyushkin T, Resch U et al (2019) Mitochondria are a subset of extracellular vesicles released by activated monocytes and induce type I IFN and TNF responses in endothelial cells. Circ Res 125:43–52. https://doi.org/10.1161/circresaha.118.314601 Quail DF, Joyce JA (2017) The microenvironmental landscape of brain tumors. Cancer Cell 31:326–341. https://doi.org/10.1016/j.ccell.2017.02.009 Rak J (1989) Possible role of tumour stem-end cell cooperation in metastasis. Med Hypotheses 29:17–19. https://doi.org/10.1016/0306-9877(89)90160-6 Rak J (2013) Extracellular vesicles–biomarkers and effectors of the cellular interactome in cancer. Front Pharmacol 4:21. https://doi.org/10.3389/fphar.2013.00021 Rak J, Mitsuhashi Y, Bayko L et al (1995) Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55:4575–4580 Revesz L (1956) Effect of tumour cells killed by x-rays upon the growth of admixed viable cells. Nature 178:1391–1392. https://doi.org/10.1038/1781391a0 Rong Y, Post DE, Pieper RO et al (2005) PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 65:1406–1413. https://doi.org/10.1158/0008-5472 Roy S, Lin HY, Chou CY et al (2019) Navigating the landscape of tumor extracellular vesicle heterogeneity. Int J Mol Sci 20:1349. https://doi.org/10.3390/ijms20061349 Royo F, Théry C, Falcón-Pérez JM et al (2020) Methods for separation and characterization of extracellular vesicles: results of a worldwide survey performed by the isev rigor and standardization subcommittee. Cells 9:1955. https://doi.org/10.3390/cells9091955 Schwartzentruber J, Korshunov A, Liu XY et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231. https://doi.org/10.1038/nature10833 Sezgin E, Levental I, Mayor S et al (2017) The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat Rev Mol Cell Biol 18:361–374. https://doi.org/10.1038/nrm.2017.16 Shao H, Chung J, Balaj L et al (2012) Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med 18:1835–1840. https://doi.org/10.1038/nm.2994 Shao H, Chung J, Lee K et al (2015) Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat Commun 6:6999. https://doi.org/10.1038/ncomms7999 Shao H, Im H, Castro CM et al (2018) New technologies for analysis of extracellular vesicles. Chem Rev 118:1917–1950. https://doi.org/10.1021/acs.chemrev.7b00534 Shin Y, Brangwynne CP (2017) Liquid phase condensation in cell physiology and disease. Science 357:eaaf4382. https://doi.org/10.1126/science.aaf4382 Sidhom K, Obi PO, Saleem A (2020) A review of exosomal isolation methods: is size exclusion chromatography the best option? Int J Mol Sci 21:6466. https://doi.org/10.3390/ijms21186466 Skog J, Wurdinger T, van Sjoerd R et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476. https://doi.org/10.1038/ncb1800 Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458. https://doi.org/10.1016/j.ccr.2004.09.028 Spinelli C, Montermini L, Meehan B et al (2018) Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell-stimulating activities. J Extracell Vesicles 7:1490144. https://doi.org/10.1080/20013078.2018.1490144 Stoner SA, Duggan E, Condello D et al (2016) High sensitivity flow cytometry of membrane vesicles. Cytometry A 89:196–206. https://doi.org/10.1002/cyto.a.22787 Szabó GT, Tarr B, Pálóczi K et al (2014) Critical role of extracellular vesicles in modulating the cellular effects of cytokines. Cell Mol Life Sci 71:4055–4067. https://doi.org/10.1007/s00018-014-1618-z Takamori S, Holt M, Stenius K et al (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846. https://doi.org/10.1016/j.cell.2006.10.030 Tauro BJ, Mathias RA, Greening DW et al (2013) Oncogenic H-Ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Mol Cell Proteomics 12:2148–2159. https://doi.org/10.1074/mcp.M112.027086 Tawil N, Bassawon R, Rak J (2019) Oncogenes and clotting factors: the emerging role of tumor cell genome and epigenome in cancer-associated thrombosis. Semin Thromb Hemost 45:373–384. https://doi.org/10.1055/s-0039-1687891 Tawil N, Bassawon R, Meehan B et al (2021) Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles. Blood Adv 5:1682–1694. https://doi.org/10.1182/bloodadvances.2020002998 Théry C, Witwer KW, Aikawa E et al (2018) Minimal information for studies of extracellular vesicles 2018 (MISEV2018): 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 van der Pol E, van Gemert MJ, Sturk A et al (2012) Single vs. swarm detection of microparticles and exosomes by flow cytometry. J Thromb Haemost 10:919–930. https://doi.org/10.1111/j.1538-7836.2012.04683.x van der Vlist EJ, Nolte-’t Hoen EN, Stoorvogel W et al (2012) Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nat Protoc 7:1311–1326. https://doi.org/10.1038/nprot.2012.065 van Niel G, D’Angelo G, Raposo G (2018) Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19:213–228. https://doi.org/10.1038/nrm.2017.125 Varn FS, Johnson KC, Martinek J et al (2022) Glioma progression is shaped by genetic evolution and microenvironment interactions. Cell 185:2184-2199.e16. https://doi.org/10.1016/j.cell.2022.04.038 Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C et al (2014) Sorting it out: regulation of exosome loading. Semin Cancer Biol 28:3–13. https://doi.org/10.1016/j.semcancer.2014.04.009 Wang Q, Hu B, Hu X et al (2017) Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 32:42-56.e6. https://doi.org/10.1016/j.ccell.2017.06.003 Wang X, Prager BC, Wu Q et al (2018) Reciprocal signaling between glioblastoma stem cells and differentiated tumor cells promotes malignant progression. Cell Stem Cell 22:514-528.e5. https://doi.org/10.1016/j.stem.2018.03.011 Wang X, Wilkinson R, Kildey K et al (2021) Molecular and functional profiling of apical versus basolateral small extracellular vesicles derived from primary human proximal tubular epithelial cells under inflammatory conditions. J Extracell Vesicles 10:e12064. https://doi.org/10.1002/jev2.12064 Welsh JA, Van Der Pol E, Arkesteijn GJA et al (2020a) MIFlowCyt-EV: a framework for standardized reporting of extracellular vesicle flow cytometry experiments. J Extracell Vesicles 9:1713526. https://doi.org/10.1080/20013078.2020.1713526 Welsh JA, van der Pol E, Bettin BA et al (2020b) Towards defining reference materials for measuring extracellular vesicle refractive index, epitope abundance, size and concentration. J Extracell Vesicles 9:1816641. https://doi.org/10.1080/20013078.2020.1816641 Whiteside TL (2016) Exosomes and tumor-mediated immune suppression. J Clin Invest 126:1216–1223. https://doi.org/10.1172/jci81136 Willms E, Cabañas C, Mäger I et al (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 Witwer KW, Goberdhan DC, O’Driscoll L et al (2021) Updating MISEV: evolving the minimal requirements for studies of extracellular vesicles. J Extracell Vesicles 10:e12182. https://doi.org/10.1002/jev2.12182 Wortzel I, Dror S, Kenific CM et al (2019) Exosome-mediated metastasis: communication from a distance. Dev Cell 49:347–360. https://doi.org/10.1016/j.devcel.2019.04.011 Xu R, Rai A, Chen M et al (2018) Extracellular vesicles in cancer–implications for future improvements in cancer care. Nat Rev Clin Oncol 15:617–638. https://doi.org/10.1038/s41571-018-0036-9 Yokoi A, Ochiya T (2021) Exosomes and extracellular vesicles: rethinking the essential values in cancer biology. Semin Cancer Biol 74:79–91. https://doi.org/10.1016/j.semcancer.2021.03.032 Yu S, Yu L (2021) Migrasome biogenesis and functions. FEBS J 289:7246–7254. https://doi.org/10.1111/febs.16183 Yu JL, May L, Lhotak V et al (2005) Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 105:1734–1741. https://doi.org/10.1182/blood-2004-05-2042 Zhang H, Freitas D, Kim HS et al (2018) Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol 20:332–343. https://doi.org/10.1038/s41556-018-0040-4 Zhang Q, Jeppesen DK, Higginbotham JN et al (2021) Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets. Nat Cell Biol 23:1240–1254. https://doi.org/10.1038/s41556-021-00805-8 Zhao S, Allis CD, Wang GG (2021) The language of chromatin modification in human cancers. Nat Rev Cancer 21:413–430. https://doi.org/10.1038/s41568-021-00357-x Zijlstra A, Di Vizio D (2018) Size matters in nanoscale communication. Nat Cell Biol 20:228–230. https://doi.org/10.1038/s41556-018-0049-8