Weill Cornell School of Medicine, New York, NY 10021, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH 44022, USA.
Neoplasia. 2022 Jun;28:100790. doi: 10.1016/j.neo.2022.100790. Epub 2022 Apr 7.
Mutations in IDH1 and IDH2 drive the development of gliomas. These genetic alterations promote tumor cell renewal, disrupt differentiation states, and induce stem-like properties. Understanding how this phenotypic reprogramming occurs remains an area of high interest in glioma research. Previously, we showed that IDH mutation results in the development of a CD24-positive cell population in gliomas. Here, we demonstrate that this CD24-positive population possesses striking stem-like properties at the molecular and phenotypic levels. We found that CD24 expression is associated with stem-like features in IDH-mutant tumors, a patient-derived gliomasphere model, and a neural stem cell model of IDH1-mutant glioma. In orthotopic models, CD24-positive cells display enhanced tumor initiating potency compared to CD24-negative cells. Furthermore, CD24 knockdown results in changes in cell viability, proliferation rate, and gene expression that closely resemble a CD24-negative phenotype. Our data demonstrate that induction of a CD24-positive population is one mechanism by which IDH-mutant tumors acquire stem-like properties. These findings have significant implications for our understanding of the molecular underpinnings of IDH-mutant gliomas.
IDH1 和 IDH2 的突变驱动了胶质瘤的发展。这些遗传改变促进肿瘤细胞更新、破坏分化状态，并诱导干细胞样特性。了解这种表型重编程是如何发生的，仍然是胶质瘤研究的一个热点领域。以前，我们表明 IDH 突变导致胶质瘤中出现 CD24 阳性细胞群体。在这里，我们证明了这个 CD24 阳性群体在分子和表型水平上具有显著的干细胞样特性。我们发现 CD24 表达与 IDH 突变肿瘤、患者来源的胶质瘤球体模型和 IDH1 突变胶质瘤的神经干细胞模型中的干细胞样特征相关。在原位模型中，CD24 阳性细胞比 CD24 阴性细胞显示出增强的肿瘤起始能力。此外，CD24 敲低导致细胞活力、增殖率和基因表达的变化，与 CD24 阴性表型非常相似。我们的数据表明，CD24 阳性群体的诱导是 IDH 突变肿瘤获得干细胞样特性的一种机制。这些发现对我们理解 IDH 突变型胶质瘤的分子基础具有重要意义。
