title: Mesenchymal stem cells secretomes' affect multiple myeloma translation initiation.
abstract: Bone marrow mesenchymal stem cells' (BM-MSCs) role in multiple myeloma (MM) pathogenesis is recognized. Recently, we have published that co-culture of MM cell lines with BM-MSCs results in mutual modulation of phenotype and proteome (via translation initiation (TI) factors eIF4E/eIF4GI) and that there are differences between normal donor BM-MSCs (ND-MSCs) and MM BM-MSCs (MM-MSCs) in this crosstalk. Here, we aimed to assess the involvement of soluble BM-MSCs' (ND, MM) components, more easily targeted, in manipulation of MM cell lines phenotype and TI with specific focus on microvesicles (MVs) capable of transferring critical biological material. We applied ND and MM-MSCs 72h secretomes to MM cell lines (U266 and ARP-1) for 12-72h and then assayed the cells' (viability, cell count, cell death, proliferation, cell cycle, autophagy) and TI (factors: eIF4E, teIF4GI; regulators: mTOR, MNK1/2, 4EBP; targets: cyclin D1, NFκB, SMAD5, cMyc, HIF1α). Furthermore, we dissected the secretome into >100kDa and <100kDa fractions and repeated the experiments. Finally, MVs were isolated from the ND and MM-MSCs secretomes and applied to MM cell lines. Phenotype and TI were assessed. Secretomes of BM-MSCs (ND, MM) significantly stimulated MM cell lines' TI, autophagy and proliferation. The dissected secretome yielded different effects on MM cell lines phenotype and TI according to fraction (>100kDa- repressed; <100kDa- stimulated) but with no association to source (ND, MM). Finally, in analyses of MVs extracted from BM-MSCs (ND, MM) we witnessed differences in accordance with source: ND-MSCs MVs inhibited proliferation, autophagy and TI whereas MM-MSCs MVs stimulated them. These observations highlight the very complex communication between MM and BM-MSCs and underscore its significance to major processes in the malignant cells. Studies into the influential MVs cargo are underway and expected to uncover targetable signals in the regulation of the TI/proliferation/autophagy cascade.
authors.affiliation: Oncogenetic Laboratory, Tel Aviv University, Tel Aviv, Israel; Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Marcus
authors.affiliation: Oncogenetic Laboratory, Tel Aviv University, Tel Aviv, Israel; Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Attar-Schneider
authors.affiliation: Oncogenetic Laboratory, Tel Aviv University, Tel Aviv, Israel; Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Dabbah
authors.affiliation: Oncogenetic Laboratory, Tel Aviv University, Tel Aviv, Israel; Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Zismanov
authors.affiliation: Oncogenetic Laboratory, Tel Aviv University, Tel Aviv, Israel; Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Tartakover-Matalon
authors.affiliation: Oncogenetic Laboratory, Tel Aviv University, Tel Aviv, Israel; Internal Medicine Department, Meir Medical Center, Kfar Saba, Tel Aviv University, Tel Aviv, Israel; Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Lishner
authors.affiliation: Oncogenetic Laboratory, Tel Aviv University, Tel Aviv, Israel; Sackler faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: druckerl@clalit.org.il.
authors.forename: L
authors.initials: L
authors.lastname: Drucker
mesh_terms: D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010442:Peptide Chain Initiation, Translational
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G
keywords: Microvesicles; Multiple myeloma; Translation initiation; bone marrow mesenchymal stem cells (BM-MSCs); eIF4E; eIF4GI