Stem Cell Unit, Department of Research and Advance Cancer Diagnostic, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy.
Department of Life Sciences, University of Trieste, 34151 Trieste, Italy.
Cells. 2023 Jul 26;12(15):1935. doi: 10.3390/cells12151935.
Multiple myeloma (MM) is an aggressive malignancy that shapes, during its progression, a pro-tumor microenvironment characterized by altered protein secretion and the gene expression of mesenchymal stem cells (MSCs). In turn, MSCs from MM patients can exert an high pro-tumor activity and play a strong immunosuppressive role. Here, we show, for the first time, greater cell mobility paralleled by the activation of FilaminA (FLNA) in MM-derived MSCs, when compared to healthy donor (HD)-derived MSCs. Moreover, we suggest the possible involvement of the IRE1a-FLNA axis in the control of the MSC migration process. In this way, IRE1a can be considered as a good target candidate for MM therapy, considering its pro-survival, pro-osteoclast and chemoresistance role in the MM microenvironment. Our results suggest that IRE1a downregulation could also interfere with the response of MSCs to MM stimuli, possibly preventing cell-cell adhesion-mediated drug resistance. In addition, further investigations harnessing IRE1a-FLNA interaction could improve the homing efficiency of MSC as cell product for advanced therapy applications.
多发性骨髓瘤（MM）是一种侵袭性恶性肿瘤，在其进展过程中形成了一个促肿瘤微环境，其特征是蛋白质分泌改变和间充质干细胞（MSCs）的基因表达改变。反过来，来自 MM 患者的 MSCs 可以发挥高度的促肿瘤活性并发挥强大的免疫抑制作用。在这里，我们首次表明，与来自健康供体（HD）的 MSC 相比，MM 来源的 MSC 具有更高的细胞迁移能力，并伴随着 FilaminA（FLNA）的激活。此外，我们提出了IRE1a-FLNA 轴在控制 MSC 迁移过程中的可能参与。通过这种方式，IRE1a 可以被认为是 MM 治疗的一个很好的候选靶标，因为它在 MM 微环境中具有促生存、促破骨细胞和化疗耐药性的作用。我们的结果表明，IRE1a 的下调也可能干扰 MSCs 对 MM 刺激的反应，可能防止细胞-细胞黏附介导的耐药性。此外，进一步研究 IRE1a-FLNA 相互作用可以提高 MSC 作为高级治疗应用的细胞产物的归巢效率。
