Leukocytes as a reservoir of circulating oncogenic DNA and regulatory targets of tumor‐derived extracellular vesicles
Author(s): ,
S. Chennakrishnaiah
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
B. Meehan
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
E. D'Asti
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
L. Montermini
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
T‐H. Lee
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
N. Karatzas
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
M. Buchanan
Affiliations:
Department of Oncology and Surgery, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
,
N. Tawil
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
D. Choi
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
,
M. Divangahi
Affiliations:
Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Meakins‐Christie Laboratories, Montreal, Canada
,
M. Basik
Affiliations:
Department of Oncology and Surgery, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
J. Rak
Affiliations:
Research Institute of the McGill University Health Centre, Glen Site, McGill University, Montreal, Canada
Correspondence: Janusz Rak, Department of Pediatrics, McGill University, 4060 Ste Catherine West, Montreal, Quebec, H3Z 2Z3 Canada|Tel.: +1 514 412 4400 ext 22342|E‐mail: janusz.rak@mcgill.ca
ISTH Academy. Rak J. Sep 4, 2018; 230959
Janusz Rak
Janusz Rak

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Journal Abstract
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Background
Tumor‐derived extracellular vesicles (EVs) and free nucleosomes (NSs) carry into the circulation a wealth of cancer‐specific, bioactive and poorly understood molecular cargoes, including genomic DNA (gDNA).
Objective
Here we investigated the distribution of extracellular oncogenic gDNA sequences (HRAS and HER2) in the circulation of tumor‐bearing mice.
Methods and Results
Surprisingly, circulating leukocytes (WBCs), especially neutrophils, contained the highest levels of mutant gDNA, which exceeded the amount of this material recovered from soluble fractions of plasma, circulating EVs, platelets, red blood cells (RBCs) and peripheral organs, as quantified by digital droplet PCR (ddPCR). Tumor excision resulted in disappearance of the WBC‐associated gDNA signal within 2–9 days, which is in line with the expected half‐life of these cells. EVs and nucleosomes were essential for the uptake of tumor‐derived extracellular DNA by neutrophil‐like cells and impacted their phenotype. Indeed, the exposure of granulocytic HL‐60 cells to EVs from HRAS‐driven cancer cells resulted in a selective increase in tissue factor (TF) procoagulant activity and interleukin 8 (IL‐8) production. The levels of circulating thrombin‐antithrombin complexes (TAT) were markedly elevated in mice harboring HRAS‐driven xenografts.
Conclusions
Myeloid cells may represent a hitherto unrecognized reservoir of cancer‐derived, EV/NS‐associated oncogenic gDNA in the circulation, and a possible novel platform for liquid biopsy in cancer. In addition, uptake of this material alters the phenotype of myeloid cells, induces procoagulant and proinflammatory activity and may contribute to systemic effects associated with cancer.
Keyword(s)
extracellular vesicles, neutrophils, nucleosomes, oncogenes, thrombosis
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