Abstract

EVs as Cancer Biomarkers

Dolores Di Vizio, Professor, Cedars Sinai Medical Center

Our group and others have demonstrated that cancer cells release oncogenic cargo in extracellular vesicles (EVs). Transit of EVs through tissue spaces can alter the tumor microenvironment and elicit behavioral responses by cells exposed to them, such as cell motility, invasiveness and metastatic propensity. These discoveries point 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. Several approaches toward development of a “liquid biopsy” for cancer have been attempted. It has been known for years that both DNA and RNA can be detected in the circulation, and that circulating, cell-free (cf) DNA is more abundant in cancer patients than in controls, and can be an indicator of resistance to therapeutic regimens. Circulating DNA is also present in EVs derived from normal and tumor cells. The possibility that EVs preserve the stability of extracellular nucleic acid in the bloodstream is stimulating efforts to use EV fraction(s) in blood as a non-invasive source of personalized markers of disease aggressiveness, and as a means of following cancer progression and regression in real time. Our team recently reported that silencing of the gene encoding the cytoskeletal regulator Diaphanous related formin-3, DIAPH3, in tumor cells results in a transition to a rapid migratory phenotype characterized by dynamic membrane perturbations and increased metastatic potential. We also discovered that DIAPH3 silencing results in the export of large (1-10 µm diameter) bioactive EVs (large oncosomes) that originate from the shedding of bulky membrane protrusions from the plasma membrane. We have demonstrated that the abundance of large oncosomes in the circulation and in tissues correlate with advanced disease in mouse models and human subjects. Large-scale profile analyses (mass spectrometry, miRNA arrays and next gen