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Maria Antonia Frassanito1, Vanessa Desantis2, Lucia Di Marzo2
1Department of Biomedical Sciences and Human Oncology, Unit of General Pathology, University of Bari Aldo Moro Medical School, Bari, Italy.
Abstract:
Aberrant microRNA (miR) expression has an important role in tumour progression, but its involvement in bone marrow fibroblasts of multiple myeloma patients remains undefined. We demonstrate that a specific miR profile in bone marrow fibroblasts parallels the transition from monoclonal gammopathy of undetermined significance (MGUS) to myeloma. Overexpression of miR-27b-3p and miR-214-3p triggers proliferation and apoptosis resistance in myeloma fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways, respectively. Transient transfection of miR-27b-3p and miR-214-3p inhibitors demonstrates a cooperation between these two miRNAs in the expression of the anti-apoptotic factor MCL1, suggesting that miR-27b-3p and miR-214-3p negatively regulate myeloma fibroblast apoptosis. Furthermore, myeloma cells modulate miR-27b-3p and miR-214-3p expression in fibroblasts through the release of exosomes. Indeed, tumour cell-derived exosomes induce an overexpression of both miRNAs in MGUS fibroblasts not through a simple transfer mechanism but by de novo synthesis triggered by the transfer of exosomal WWC2 protein that regulates the Hippo pathway. Increased levels of miR-27b-3p and miR-214-3p in MGUS fibroblasts co-cultured with myeloma cell-derived exosomes enhance the expression of fibroblast activation markers αSMA and FAP. These data show that the MGUS-to-myeloma transition entails an aberrant miRNA profile in marrow fibroblasts and highlight a key role of myeloma cells in modifying the bone marrow microenvironment by reprogramming the marrow fibroblasts' behaviour. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Insights
Aberrant microRNA (miR) profiles in bone marrow fibroblasts are linked to multiple myeloma progression. Myeloma cells reprogram these fibroblasts via exosomes, driving disease advancement.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Aberrant microRNA (miR) expression is implicated in cancer progression.
- The role of miRs in bone marrow fibroblasts during multiple myeloma (MM) development is not well understood.
Purpose of the Study:
- To investigate the specific miR profile in bone marrow fibroblasts during the transition from monoclonal gammopathy of undetermined significance (MGUS) to MM.
- To elucidate the mechanisms by which myeloma cells influence bone marrow fibroblasts.
Main Methods:
- Analysis of miR expression in bone marrow fibroblasts from MGUS and MM patients.
- Overexpression and inhibition studies of specific miRs (miR-27b-3p, miR-214-3p) in fibroblasts.
- Exosome isolation and characterization from myeloma cells.
- Co-culture experiments with MGUS fibroblasts and myeloma cell-derived exosomes.
- Western blot analysis for protein expression (FBXW7, PTEN, AKT, GSK3, MCL1, WWC2, αSMA, FAP).
Main Results:
- A distinct miR profile in bone marrow fibroblasts correlates with the MGUS-to-MM transition.
- Overexpression of miR-27b-3p and miR-214-3p promotes fibroblast proliferation and inhibits apoptosis via specific signaling pathways (FBXW7, PTEN/AKT/GSK3).
- Myeloma cell-derived exosomes, particularly exosomal WWC2 protein, induce de novo synthesis of miR-27b-3p and miR-214-3p in MGUS fibroblasts, activating the Hippo pathway.
- Increased miR levels in fibroblasts co-cultured with exosomes enhance fibroblast activation markers (αSMA, FAP).
Conclusions:
- The MGUS-to-MM transition involves significant alterations in the bone marrow fibroblast miR profile.
- Myeloma cells actively reprogram bone marrow fibroblasts through exosome-mediated transfer of WWC2 protein, leading to increased miR expression and fibroblast activation.
- This reprogramming contributes to the modification of the bone marrow microenvironment, favoring myeloma progression.
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