Identification of Double-stranded Genomic DNA Spanning All Chromosomes with Mutated KRAS and p53 DNA in the Serum Exosomes of Patients with Pancreatic Cancer

Kahlert, Christoph; Melo, Sónia A.; Protopopov, Alexei; Tang, Jiabin; Seth, Sahil; Koch, Moritz; Zhang, Jianhua; Weitz, Juergen; Chin, Lynda; Futreal, Andrew; Kalluri, Raghu

doi:10.1074/jbc.c113.532267

Cited by 872 publications

(804 citation statements)

References 23 publications

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“…The disparity could be related to a different cellular source, or to the diversity of vesiculation processes involved in various systems. However, the ability of cancer cells to emit double-stranded DNA is consistent with several recent observations [18][19][20][21].…”

Section: Discussionsupporting

confidence: 91%

“…While the CNV plot suggests some increase in contribution of certain loci (chromosome 11 -upward shift), we have not detected any genomic regions that would be selectively included in EVs (Fig. 3C), as suggested earlier by us [18] and others [20]. Indeed, over 90% of the cellular genome was found in EVs with at least 3 times the coverage of sequences (Fig.…”

Section: Dna Contained In Extracellular Vesicles Represents the Entirsupporting

confidence: 77%

“…1). Therefore, we reasoned that H-ras sequences in this material may represent the previously reported single-stranded [8], or double-stranded [18][19][20][21] vesicular DNA.…”

Section: Resultsmentioning

confidence: 98%

“…Indeed, oncogenic DNA sequences were found in large vesicular structures known as apoptotic bodies (ABs) formed upon death of cancer cells [17]. EVs emanating from viable cancer cells were also found to contain single and double-stranded DNA [8,[18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Lee

Chennakrishnaiah

Audemard

et al. 2014

Biochemical and Biophysical Research Communications

175

189

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Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the related mechanisms of DNA release, composition and biological activity remain unclear. Here we show that rat epithelial cell transformation by the human H-ras oncogene leads to an increase in production of small, exosomal-like extracellular vesicles by viable cancer cells. These EVs contain chromatin-associated double-stranded DNA fragments covering the entire host genome, including full-length H-ras. Oncogenic N-ras and SV40LT sequences were also found in EVs emitted from spontaneous mouse brain tumour cells. Disruption of acidic sphingomyelinase and the p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of nontransformed RAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention of this material for an extended (30 days) but transient period of time, and stimulated cell proliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicular emission of this histone-bound oncogene, which may interact with non-transformed cells.

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Section: Discussionsupporting

confidence: 91%

Section: Dna Contained In Extracellular Vesicles Represents the Entirsupporting

confidence: 77%

“…1). Therefore, we reasoned that H-ras sequences in this material may represent the previously reported single-stranded [8], or double-stranded [18][19][20][21] vesicular DNA.…”

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Lee

Chennakrishnaiah

Audemard

et al. 2014

Biochemical and Biophysical Research Communications

175

189

View full text Add to dashboard Cite

show abstract

“…Additional studies indicated that the release of small EVs (S-EVs) containing gDNA is driven by specific oncogenes, which are functionally transferred to target cells via EVs [16]. Later reports discovered that exosomes (Exo) contain entire genomes with large fragments (<10,000 bp [base pair]) of dsDNA and carry mutations of parental tumour cells [11,17,18]. These data suggest diagnostic and prognostic value for EV DNA.…”

Section: Introductionmentioning

confidence: 99%

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

Vagner

Spinelli

Minciacchi

et al. 2018

J of Extracellular Vesicle

313

332

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Cancer-derived extracellular vesicles (EVs) are membrane-enclosed structures of highly variable size. EVs contain a myriad of substances (proteins, lipid, RNA, DNA) that provide a reservoir of circulating molecules, thus offering a good source of biomarkers. We demonstrate here that large EVs (L-EV) (large oncosomes) isolated from prostate cancer (PCa) cells and patient plasma are an EV population that is enriched in chromosomal DNA, including large fragments up to 2 million base pair long. While L-EVs and small EVs (S-EV) (exosomes) isolated from the same cells contained similar amounts of protein, the DNA was more abundant in L-EV, despite S-EVs being more numerous. Consistent with in vitro observations, the abundance of DNA in L-EV obtained from PCa patient plasma was variable but frequently high. Conversely, negligible amounts of DNA were present in the S-EVs from the same patients. Controlled experimental conditions, with spike-ins of L-EVs and S-EVs from cancer cells in human plasma from healthy subjects, showed that circulating DNA is almost exclusively enclosed in L-EVs. Whole genome sequencing revealed that the DNA in L-EVs reflects genetic aberrations of the cell of origin, including copy number variations of genes frequently altered in metastatic PCa (i.e. MYC, AKT1, PTK2, KLF10 and PTEN). These results demonstrate that L-EV-derived DNA reflects the genomic make-up of the tumour of origin. They also support the conclusion that L-EVs are the fraction of plasma EVs with DNA content that should be interrogated for tumour-derived genomic alterations.

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Urinary exosomal proteins as (pan‐)cancer biomarkers: insights from the proteome

et al. 2019

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Exosomes are extracellular vesicles (EVs) released from cells under both physiological and pathological conditions, and may, thus, be present in biofluids. Urine is one of the most accessible biofluids implemented in clinical diagnostics. Recent mass spectrometry (MS)‐based proteomic analyses have enabled high‐throughput, deep proteome profiling of urinary EVs for the discovery, quantification and characterization of cancer‐specific exosome biomarkers. The protein cargo of urine exosomes is emerging as an attractive source for biomarkers, not only for urological cancers, such as prostate, bladder and kidney cancer, but potentially also for nonurological cancers, including gastric, lung, oesophageal and colorectal cancer. More recently, exosome proteomics dissected protein cargo in the lumen and at the surface of EVs, and unexpectedly indicated that RNA‐ and DNA‐binding proteins might also be present on vesicular surfaces. Here, we analyse MS‐based proteomic data on urinary exosomes from cancer patients, and discuss the potential of urinary exosome‐derived biomarkers in cancer.

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Identification of Double-stranded Genomic DNA Spanning All Chromosomes with Mutated KRAS and p53 DNA in the Serum Exosomes of Patients with Pancreatic Cancer

Cited by 872 publications

References 23 publications

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

Urinary exosomal proteins as (pan‐)cancer biomarkers: insights from the proteome

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