Ribosomal proteins as distinct “passengers” of microvesicles: new semantics in myeloma and mesenchymal stem cells' communication

Mahmoud Dabbah, Michael Lishner, Osnat Jarchowsky-Dolberg, Shelly Tartakover-Matalon, Yaron S. Brin, Metsada Pasmanik-Chor, Avivit Neumann, Liat Drucker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Aberrant mesenchymal stem cells (MSCs) in multiple myeloma (MM) bone marrows (BM) promote disease progression and drug resistance. Here, we assayed the protein cargo transported from MM-MSCs to MM cells via microvesicles (MVs) with focus on ribosomal proteins (RPs) and assessment of their influence on translation initiation and design of MM phenotype. Proteomics analysis (mass spectrometry) demonstrated increased levels and repertoire of RPs in MM-MSCs MVs compared to normal donors (ND) counterparts (n = 3–8; P = 9.96E − 08). We limited the RPs load in MM-MSCs MVs (starvation, RSK and XPO1 inhibitions), reapplied the modified MVs to MM cell lines (U266, MM1S), and demonstrated that the RPs are essential to the proliferative effect of MM-MSCs MVs on MM cells (n = 3; P < 0.05). We also observed that inhibition with KPT-185 (XPO1 inhibitor) displayed the most extensive effect on RPs delivery into the MVs (↓80%; P = 3.12E − 05). Using flow cytometry we assessed the expression of select RPs (n = 10) in BM-MSCs cell populations (ND and MM; n ≥ 6 each). This demonstrated a heterogeneous expression of RPs in MM-MSCs with distinct subgroups, a phenomenon absent from ND-MSCs samples. These findings bring to light a new mechanism in which the tumor microenvironment participates in cancer promotion. MVs-mediated horizontal transfer of RPs between niche MSCs and myeloma cells is a systemic way to bestow pro-cancer advantages. This capacity also differentiates normal MSCs from the MM-modified MSCs and may mark their reprogramming. Future studies will be aimed at assessing the clinical and therapeutic potential of the increased RPs levels in MM-MSCs MVs.

Original languageEnglish
Pages (from-to)117-132
Number of pages16
JournalTranslational Research
Volume236
DOIs
StatePublished - Oct 2021

Funding

FundersFunder number
Dotan Hemato-oncology Center
Israel Cancer Association281100124
Tel Aviv University0601243683
Sackler Faculty of Medicine, Tel-Aviv University

    Keywords

    • BM-MSCs
    • Exportin 1
    • MFI
    • MM
    • MM-MSCs
    • MSCs
    • MVs
    • ND
    • RPs
    • RSK
    • TI
    • XPO1
    • bone marrow mesenchymal stem cells
    • eIF4E
    • eIF4GI
    • eukaryotic translation initiation factor 4E
    • eukaryotic translation initiation factor 4GI
    • mean fluorescence intensity
    • mesenchymal stem cells
    • microvesicles
    • multiple myeloma
    • multiple myeloma mesenchymal stem cells
    • normal donor
    • ribosomal protein S6 kinases (p90RSK)
    • ribosomal proteins
    • translation initiation

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