oa Tunneling nanotubes mediate preferential transfer of mitochondria from endothelial to cancer cells and confer chemoresistance

Many tumors are regulated by complex interactions with cellular components of the microenvironment including mesenchymal stem cells (MSC) or endothelial cells (ECs). While the role of receptor-ligand interaction at the cell surface is well documented, direct cell-to-cell contact has not been clearly established. Recently, tunneling nanotubes (TnTs) have been shown to support cell-to-cell transfer of organelles, various plasma membrane components and cytoplasmic molecules in several cell lines. We thus investigated the formation of TnTs between stromal cells and cancer cells supported by them. We demonstrate that TnTs occur between different cancer and stromal cell lines. TnTs formation seemed to be dependent of large membrane adhesion. We show that intercellular transfers of cytoplasmic content can occur by TnTs. However, we demonstrate that the exchange of mitochondria occurs preferentially between endothelial cells and cancer cells and contributes to chemoresistance. Our results point out the role of direct endothelial to cancer cell exchange, which emphasize our hypothesis that this angiogenesis-independent role of the endothelium plays a role in the constitution of the metastatic niche.