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

Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the relatedmechanisms of DNA release, composition and biological activity remain unclear. Here we showthat rat epithelial cell transformation by the human H-ras oncogene leads to an increase inproduction of small, exosomal-like extracellular vesicles by viable cancer cells. These EVscontain 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 EVsemitted from spontaneous mouse brain tumour cells. Disruption of acidic sphingomyelinase andthe p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of nontransformedRAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention ofthis material for an extended (30 days) but transient period of time, and stimulated cellproliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicularemission of this histone-bound oncogene, which may interact with non-transformed cells