Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
J Pathol. 2019 Nov;249(3):295-307. doi: 10.1002/path.5317. Epub 2019 Aug 31.
Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma-initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy-resistant MES-like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single-cell level and strongly correlated with our previously defined therapy-resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy-resistant MES-like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long-term exposure to the proinflammatory cytokine interleukin 1 beta (IL1β). IL1β induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive-astrocyte-like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called 'reactive GICs'. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor-promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment-resistant relapse-driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
IV 级星形细胞瘤/胶质母细胞瘤（GBM）基本上是无法治愈的，部分原因是其异质性，即使在神经胶质瘤起始细胞（GIC）群体中也是如此。GIC 的治疗抵抗性增加与向间充质（MES）细胞状态的转变有关。GBM 的 MES 分子特征表现出明显的炎症特征，其表达在肿瘤内和肿瘤间存在差异。在此，我们研究了 GBM 细胞的 MES 转变与正常星形胶质细胞的炎症反应之间的关系。在中枢神经系统损伤后，星形胶质细胞进入反应性细胞状态，并参与指导神经炎症和随后的愈合过程。我们发现 MES 特征与反应性星形胶质细胞中诱导的基因程序具有很强的相似性。同样，星形胶质细胞反应性基因特征在具有治疗抵抗性的 MES 样 GIC 克隆中富集。星形胶质细胞反应性相关基因的可变表达也在很大程度上定义了单细胞水平的肿瘤内 GBM 细胞异质性，并与我们之前定义的治疗抵抗性特征（基于 GIC 克隆的分子和功能特征的关联）强烈相关。与此一致的是，具有治疗抵抗性的 MES 样 GIC 分泌与星形胶质细胞反应性相关的免疫调节和组织修复相关蛋白。此外，通过长期暴露于促炎细胞因子白细胞介素 1β（IL1β），可以使敏感的 GIC 克隆变得具有反应性。IL1β 诱导缓慢的 MES 转变，增加治疗抵抗性，并使 DNA 甲基化谱向耐药克隆转变，这证实了一个缓慢的重编程过程。总之，GIC 通过 MES 转变进入反应性星形胶质细胞样细胞状态，与治疗抵抗有关。因此，从生物学的角度来看，MES GIC 最好被称为“反应性 GIC”。GBM 细胞模拟星形胶质细胞反应性的能力使 GBM 细胞具有免疫调节和重塑微环境的能力，从而产生促进肿瘤生长的环境。这一见解对于指导针对治疗抵抗性复发驱动细胞群体的未来增敏治疗以及提高 GBM 免疫疗法的效率都将是重要的。
