title: Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance.
abstract: Our vision of cancer has changed during the past decades. Indeed tumors are now perceived as complex entities where tumoral and stromal components interact closely. Among the different elements of tumor stroma the cellular component play a primordial role. Bone Marrow derived mesenchymal cells (MSCs) are attracted to tumor sites and support tumor growth. Endothelial cells (ECs) play a major role in angiogenesis. While the literature documents many aspects of the cross talk between stromal and cancer cells, the role of direct hetero-cellular contact is not clearly established. Recently, Tunneling nanotubes (TnTs) have been shown to support cell-to-cell transfers of plasma membrane components, cytosolic molecules and organelles within cell lines. Herein, we have investigated the formation of heterocellular TnTs between stromal (MSCs and ECs) and cancer cells. We demonstrate that TnTs occur between different cancer cells, stromal cells and cancer-stromal cell lines. We showed that TnTs-like structure occurred in 3D anchorage independent spheroids and also in tumor explant cultures. In our culture condition, TnTs formation occurred after large membrane adhesion. We showed that intercellular transfers of cytoplasmic content occurred similarly between cancer cells and MSCs or ECs, but we highlighted that the exchange of mitochondria occurred preferentially between endothelial cells and cancer cells. We illustrated that the cancer cells acquiring mitochondria displayed chemoresistance. Our results illustrate the perfusion-independent role of the endothelium by showing a direct endothelial to cancer cell mitochondrial exchange associated to phenotypic modulation. This supports another role of the endothelium in the constitution of the metastatic niche.
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha PO: 24144, Qatar.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pasquier
authors.forename: Bella S
authors.initials: BS
authors.lastname: Guerrouahen
authors.forename: Hamda
authors.initials: H
authors.lastname: Al Thawadi
authors.forename: Pegah
authors.initials: P
authors.lastname: Ghiabi
authors.forename: Mahtab
authors.initials: M
authors.lastname: Maleki
authors.forename: Nadine
authors.initials: N
authors.lastname: Abu-Kaoud
authors.forename: Arthur
authors.initials: A
authors.lastname: Jacob
authors.forename: Massoud
authors.initials: M
authors.lastname: Mirshahi
authors.forename: Ludovic
authors.initials: L
authors.lastname: Galas
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: Frank
authors.initials: F
authors.lastname: Le Foll
authors.forename: Arash
authors.initials: A
authors.lastname: Rafii
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D018920:Coculture Techniques / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008928:Mitochondria / Q000378:metabolism*; D043942:Nanotubes / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D049452:Green Fluorescent Proteins