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

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. Background: Others and we have demonstrated the significant role for BM mesenchymal stem cells in design of MM phenotype and drug response. The participation of microvesicles in this dialogue and the manipulation of translation initiation is also established. These observations also point to a fundamental difference between BM-MSCs according to their origin from healthy or pathological niches. Translational Significance: By mass spectrometry analysis we provide insight into the aberrant expression of ribosomal proteins in MM-MSCs microvesicles and highlight a marker of niche reprogramming and new mechanism of MM design. These observations may afford unique and selective opportunities for therapeutic intervention.