Heinemann Luca, Möllers Klara Maria, Ahmed Helal Mohammed Mohammed, Wei Lanying, Sun Kaiyan, Nimmagadda Subbaiah Chary, Frank Daria, Baumann Anja, Poos Alexandra M, Dugas Martin, Varghese Julian, Raab Marc-Steffen, Khandanpour Cyrus
Medical Department A, University Hospital Münster, Münster, Germany.
Institute of Medical Informatics, University of Münster, Münster, Germany.
Front Oncol. 2022 Jun 20;12:874325. doi: 10.3389/fonc.2022.874325. eCollection 2022.
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.
癌细胞的微环境作为影响肿瘤疾病进展和预后的重要因素，正受到越来越多的关注。在多发性骨髓瘤（MM），一种浆细胞血液系统癌症中，间充质干细胞（MSCs）是骨髓生态位和肿瘤微环境的一个组成部分。已有研究表明，MM细胞以一种MM相关的MSCs促进MM细胞增殖和存活的方式改变MSCs。然而，我们对控制MM细胞与MSCs之间相互作用的分子机制以及这是否可作为治疗干预靶点的理解有限。为了确定潜在的分子靶点，我们通过RNA测序和蛋白质印迹分析对MSCs进行了检测。我们报告，与来自其他（非）恶性疾病患者的MSCs（CTR-MSCs）相比，来自患有活动性疾病的MM患者的MSCs（MM-Act-MSCs）显示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标志性基因集的显著富集，并进一步证实了这些MSCs中相关蛋白水平的升高。泛PI3K抑制剂pictilisib与CTR-MSCs相比，选择性地降低了MM-Act-MSCs的增殖。此外，pictilisib治疗损害了MM-Act-MSCs促进MM的功能。因此，我们的数据为与MM相关的MSCs的分子特征和功能提供了更深入的见解，并表明靶向MSCs中的PI3K-AKT-mTOR信号通路可能代表了治疗MM患者的另一种治疗途径。
