Transcriptome changes due to nuclear penetration of cancer extracellular vesicles

Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication in autocrine or paracrine manner. We report that cancer-derived EV biomaterials reach nuclei of human melanoma and breast carcinoma cells and multipotent mesenchymal stromal cells (MSCs) through Rab7+ late endosome subdomains that penetrate into nuclear envelope invaginations. MSCs were exposed to cancer Evs in the presence or absence of drugs that block nucler import or export through the nuclear pores. Depletion of CD9 or inhibition of importin ß1, two EV-associated molecules, abrogated the nuclear localization of EV-derived biomaterials and EV-induced early changes in MSC transcriptome notably in genes involved in inflammation. Also inhibition of nuclear export by leptomycin B inhibited early changes in MSC transcriptome. This novel cellular pathway may become a cancer therapeutic target. Overall design: mRNA-Seq Human mesenchymal stromal cells alone or exposed to cancer Evs in the presence or absence of uptake modulators