OAB-041: Epithelial-mesenchymal-transition regulated by Junctional Adhesion Molecule-A (JAM-A) associates with aggressive extramedullary multiple myeloma disease
Clinical Lymphoma Myeloma and Leukemia(2021)
Abstract
Background Interactions between multiple myeloma plasma cells (MMPC) and the multiple myeloma (MM) niche control cell proliferation, drug resistance, and disease spreading through various adhesion molecules and chemokine receptors. Among these, junctional adhesion molecule-A (JAM-A) mediates MMPC-endothelial interactions and propagates neovascularization. Here we addressed whether JAM-A signaling mediates MMPC invasive behavior orchestrating intra- and extramedullary MM dissemination. Methods We investigated JAM-A expression with flow cytometry and immunohistochemistry in 60 MM patient bone marrow (BM) aspirates and biopsies at different disease stages with and without extramedullary disease (EMD) manifestation. We compared these results with RNA-Seq data from 647 newly diagnosed MM (NDMM) patients collected in the MMRF CoMMpass study. Using bioinformatics, we investigated JAM-A-related pathways with hierarchical cluster analysis. Subsequently, we functionally validated these JAM-A-related pathways regarding epithelial-mesenchymal transition (EMT), invasion, and MM dissemination in vitro. Results The median OS differed significantly in subjects with elevated membrane JAM-A expression levels, dividing the patients in the EMD JAM-Ahigh group with a median OS of 84.1 months, whereas median OS in JAM-Alow patients was not reached, irrespective of the EMD status (log-rank=4.19, P=.04). Immunohistochemistry analysis of BM biopsies confirmed these findings. RNA-Seq analysis corroborated the prognostic impact of JAM-A (log-rank=3.8, P=.051). High-risk patients with EMD and JAM-A expression displayed a unique gene-expression signature. Additionally, we constructed a novel expression cluster subgroup model, revealing complex molecular disease patterns and associations between clinical traits and expression markers. Strikingly, MM patients clustered by JAM-A expression levels and EMD manifestation revealed properties of epithelial-mesenchymal-transition and induced focal adhesion pathways. Notably, functional knockdown of JAM-A in MMPC in vitro not only reduced cell viability but also diminished MMPC adhesion molecules and CD138 surface expression. Furthermore, mTOR/PI3K in vitro inhibition with BEZ235 significantly downregulated surface expression in JAM-Ahigh MM cells. Interestingly, when we inhibited mTOR/PI3K in JAM-Alow MM cells, we observed JAM-A induction. Finally, ensuing functional shRNA knockdown of JAM-A halted MM invasion (P Conclusions Collectively, these data reveal JAM-A-mediated signaling critical for EMT transition and invasive behavior. Based on these findings we propose JAM-A as a promising biomarker and novel theragnostic target in MM patients.
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Key words
multiple myeloma,epithelial-mesenchymal-transition epithelial-mesenchymal-transition
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