Loftus Alexander E P, Romano Marianna S, Phuong Anh Nguyen, McKinnel Ben J, Muir Morwenna T, Furqan Muhammad, Dawson John C, Avalle Lidia, Douglas Adam T, Mort Richard L, Byron Adam, Carragher Neil O, Pollard Steven M, Brunton Valerie G, Frame Margaret C
Cancer Research UK Scotland Centre (Edinburgh), Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK.
Cancer Research UK Scotland Centre (Edinburgh), Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK.
Dev Cell. 2024 Dec 16;59(24):3197-3212.e7. doi: 10.1016/j.devcel.2024.09.003. Epub 2024 Sep 25.
Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumor progression and therapeutic resistance. Here, we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) stimulates phenotypic plasticity and mesenchymal-like, invasive behavior in a murine GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss produces cells that are unresponsive to multiple cell state transition cues. We further show that an ILK/STAT3 signaling pathway controls the plasticity that enables transition of GBM stem cells to an astrocyte-like state in vitro and in vivo. Finally, we find that ILK expression correlates with expression of STAT3-regulated proteins and protein signatures describing astrocyte-like and mesenchymal states in patient tumors. This work identifies ILK as a pivotal regulator of multiple malignancy-associated GBM phenotypes, including phenotypic plasticity and mesenchymal state.
胶质母细胞瘤（GBM）由恶性神经干细胞样细胞驱动，这些细胞表现出广泛的异质性和表型可塑性，从而推动肿瘤进展和治疗抗性。在此，我们表明细胞外基质-细胞粘附蛋白整合素连接激酶（ILK）在小鼠GBM干细胞模型中刺激表型可塑性和间充质样侵袭行为。ILK是GBM干细胞在恶性相关神经胶质样状态之间相互转化所必需的，其缺失会产生对多种细胞状态转变信号无反应的细胞。我们进一步表明，ILK/STAT3信号通路控制着可塑性，使GBM干细胞在体外和体内能够转变为星形胶质细胞样状态。最后，我们发现ILK表达与患者肿瘤中STAT3调节蛋白的表达以及描述星形胶质细胞样和间充质状态的蛋白特征相关。这项工作确定ILK是多种恶性相关GBM表型的关键调节因子，包括表型可塑性和间充质状态。
