TY - JOUR
T1 - Ribosomal proteins as distinct “passengers” of microvesicles
T2 - new semantics in myeloma and mesenchymal stem cells' communication
AU - Dabbah, Mahmoud
AU - Lishner, Michael
AU - Jarchowsky-Dolberg, Osnat
AU - Tartakover-Matalon, Shelly
AU - Brin, Yaron S.
AU - Pasmanik-Chor, Metsada
AU - Neumann, Avivit
AU - Drucker, Liat
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
KW - BM-MSCs
KW - Exportin 1
KW - MFI
KW - MM
KW - MM-MSCs
KW - MSCs
KW - MVs
KW - ND
KW - RPs
KW - RSK
KW - TI
KW - XPO1
KW - bone marrow mesenchymal stem cells
KW - eIF4E
KW - eIF4GI
KW - eukaryotic translation initiation factor 4E
KW - eukaryotic translation initiation factor 4GI
KW - mean fluorescence intensity
KW - mesenchymal stem cells
KW - microvesicles
KW - multiple myeloma
KW - multiple myeloma mesenchymal stem cells
KW - normal donor
KW - ribosomal protein S6 kinases (p90RSK)
KW - ribosomal proteins
KW - translation initiation
UR - http://www.scopus.com/inward/record.url?scp=85106255720&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2021.04.002
DO - 10.1016/j.trsl.2021.04.002
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C2 - 33887527
AN - SCOPUS:85106255720
SN - 1931-5244
VL - 236
SP - 117
EP - 132
JO - Translational Research
JF - Translational Research
ER -