Table_1_Inhibiting PI3K–AKT–mTOR Signaling in Multiple Myeloma-Associated Mesenchymal Stem Cells Impedes the Proliferation of Multiple Myeloma Cells.xlsx

The microenvironment of cancer cells is receiving increasing attention as an important factor influencing the progression and prognosis of tumor diseases. In multiple myeloma (MM), a hematological cancer of plasma cells, mesenchymal stem cells (MSCs) represent an integral part of the bone marrow niche and tumor microenvironment. It has been described that MM cells alter MSCs in a way that MM-associated MSCs promote the proliferation and survival of MM cells. Yet, our understanding of the molecular mechanisms governing the interaction between MM cells and MSCs and whether this can be targeted for therapeutic interventions is limited. To identify potential molecular targets, we examined MSCs by RNA sequencing and Western blot analysis. We report that MSCs from MM patients with active disease (MM-Act-MSCs) show a distinct gene expression profile as compared with MSCs from patients with other (non-) malignant diseases (CTR-MSCs). Of note, we detected a significant enrichment of the PI3K–AKT–mTOR hallmark gene set in MM-Act-MSCs and further confirmed the increased levels of related proteins in these MSCs. Pictilisib, a pan-PI3K inhibitor, selectively reduced the proliferation of MM-Act-MSCs as compared with CTR-MSCs. Furthermore, pictilisib treatment impaired the MM-promoting function of MM-Act-MSCs. Our data thus provide a deeper insight into the molecular signature and function of MSCs associated with MM and show that targeting PI3K–AKT–mTOR signaling in MSCs may represent an additional therapeutic pathway in the treatment of MM patients.

癌细胞微环境作为影响肿瘤疾病进展与预后的关键因素，正受到日益广泛的关注。作为浆细胞来源的血液系统恶性肿瘤，多发性骨髓瘤（multiple myeloma, MM）中，间充质干细胞（mesenchymal stem cells, MSCs）是骨髓龛与肿瘤微环境的重要组成部分。已有研究显示，MM细胞可对MSCs进行重塑，使MM相关MSCs能够促进MM细胞的增殖与存活。然而，目前学界对于调控MM细胞与MSCs之间相互作用的分子机制，以及能否以此为靶点开展治疗干预的认知仍较为有限。为识别潜在的分子治疗靶点，我们通过RNA测序与蛋白质印迹（Western blot）分析对MSCs进行了研究。结果表明，相较于其他（非）恶性疾病患者来源的MSCs（CTR-MSCs），活动性MM患者来源的MSCs（MM-Act-MSCs）呈现出独特的基因表达谱。值得注意的是，我们在MM-Act-MSCs中检测到PI3K–AKT–mTOR特征基因集存在显著富集，并进一步验证了此类MSCs中相关蛋白的表达水平显著升高。泛PI3K抑制剂匹替利布（Pictilisib）可选择性抑制MM-Act-MSCs的增殖能力，其效果相较于CTR-MSCs更为显著。此外，经匹替利布处理后，MM-Act-MSCs的MM细胞促增殖功能受到明显削弱。综上，本研究深入阐明了MM相关MSCs的分子特征与功能，并证实靶向MSCs中的PI3K–AKT–mTOR信号通路，或可作为MM患者治疗的全新潜在途径。