Abstract

Heterogeneity of Cancer-Derived Extracellular Vesicles

Dolores Di Vizio, Professor, Cedars Sinai Medical Center

Cancer cells release oncogenic cargo in bioactive extracellular vesicles (EVs) that can alter the tumor microenvironment and elicit behavioral responses in target cells. This discovery points to a role in tumor evolution for a conserved and finely regulated biological process that allows intercellular transfer of bioactive proteins, nucleic acids and lipids in the form of pre-assembled plasma membrane structures. In the last few years, it has emerged that every cell can release different types of EVs, with selective cargo and function. Studies on exosomes, for example, have demonstrated that diverse types of exosomes can be released by tumor cells. Several new methodologies are being interrogated to differentiate between exosomes with different cargo/functions. Different populations of exosomes as well as of larger EV types including the large oncosomes could provide clinically relevant information. We have performed comparative studies of exosome and large oncosome cargo, profiling proteins and nucleic acids in the particles by mass spectrometry, whole genome sequencing and RNA sequencing. Our results indicate that the bulk of the cargo is similar in exosomes and large oncosomes derived from the same cell system. However, there are qualitative and quantitative differences that suggest that the large oncosomes could be the cancer cell-derived EV population with the strongest biological activity and the highest content in cancer-specific molecules.  Our data also suggest that large oncosomes represent valuable candidates to allow new biomarker profiles to be developed using tissue- and blood-based assays in combination. Importantly, the abundance of large oncosomes in the circulation and in tissues correlates with advanced disease in mouse models and human subjects.