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Hagey DW, Kordes M, Görgens A, et al. Extracellular vesicles are the primary source of blood-borne tumour-derived mutant KRAS DNA early in pancreatic cancer. J Extracell Vesicles. 2021;10(12):e12142doi: 10.1002/jev2.12142.
Hagey, D. W., Kordes, M., Görgens, A., Mowoe, M. O., Nordin, J. Z., Moro, C. F., Löhr, J. M., & El Andaloussi, S. (2021). Extracellular vesicles are the primary source of blood-borne tumour-derived mutant KRAS DNA early in pancreatic cancer. Journal of extracellular vesicles, 10(12), e12142. https://doi.org/10.1002/jev2.12142
Hagey, Daniel W, et al. "Extracellular vesicles are the primary source of blood-borne tumour-derived mutant KRAS DNA early in pancreatic cancer." Journal of extracellular vesicles vol. 10,12 (2021): e12142. doi: https://doi.org/10.1002/jev2.12142
Hagey DW, Kordes M, Görgens A, Mowoe MO, Nordin JZ, Moro CF, Löhr JM, El Andaloussi S. Extracellular vesicles are the primary source of blood-borne tumour-derived mutant KRAS DNA early in pancreatic cancer. J Extracell Vesicles. 2021 Oct;10(12):e12142. doi: 10.1002/jev2.12142. PMID: 34595842; PMCID: PMC8485184.
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J Extracell Vesicles. 2021 Oct;10(12):e12142. doi: 10.1002/jev2.12142.

Extracellular vesicles are the primary source of blood-borne tumour-derived mutant KRAS DNA early in pancreatic cancer.

Journal of extracellular vesicles

Daniel W Hagey, Maximilian Kordes, André Görgens, Metoboroghene O Mowoe, Joel Z Nordin, Carlos Fernández Moro, J-Matthias Löhr, Samir El Andaloussi

Affiliations

  1. Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
  2. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
  3. Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden.
  4. Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg Essen, Essen, Germany.
  5. Institute for Infectious Diseases and Molecular Medicine, Division of Chemical and Systems Biology, University of Cape Town, Cape Town, South Africa.
  6. Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
  7. Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.

PMID: 34595842 PMCID: PMC8485184 DOI: 10.1002/jev2.12142

Abstract

Up to now, the field of liquid biopsies has focused on circulating tumour DNA and cells, though extracellular vesicles (EVs) have been of increasing interest in recent years. Thus, reported sources of tumour-derived nucleic acids include leukocytes, platelets and apoptotic bodies (AB), as well as large (LEV) and small (SEV) EVs. Despite these competing claims, there has yet to be a standardized comparison of the tumour-derived DNA associated with different components of blood. To address this issue, we collected twenty-three blood samples from seventeen patients with pancreatic cancers of known mutant KRAS G12 genotype, and divided them into two groups based on the time of patient survival following sampling. After collecting red and white blood cells, we subjected 1 ml aliquots of platelet rich plasma to differential centrifugation in order to separate the platelets, ABs, LEVs, SEVs and soluble proteins (SP) present. We then confirmed the enrichment of specific blood components in each differential centrifugation fraction using electron microscopy, Western blotting, nanoparticle tracking analysis and bead-based multiplex flow cytometry assays. By targeting wild type and tumour-specific mutant KRAS alleles using digital PCR, we found that the levels of mutant KRAS DNA were highest in association with LEVs and SEVs early, and with SEVs and SP late in disease progression. Importantly, we established that SEVs were the most enriched in tumour-derived DNA throughout disease progression, and verified this association using size exclusion chromatography. This work provides important direction for the rapidly expanding field of liquid biopsies by supporting an increased focus on EVs as a source of tumour-derived DNA.

© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.

Keywords: apoptotic bodies; cancer diagnostics; ctDNA; digital PCR; exosomes; extracellular vesicles; liquid biopsy; microvesicles; pancreatic cancer; platelets

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