Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
Nat Cell Biol. 2018 Oct;20(10):1203-1214. doi: 10.1038/s41556-018-0183-3. Epub 2018 Sep 10.
Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx. Studies showed that a bulky glycocalyx potentiates integrin mechanosignalling and tissue tension and promotes a mesenchymal, stem-like phenotype in GBMs. Gain- and loss-of-function studies implicated integrin mechanosignalling as an inducer of GBM growth, survival, invasion and treatment resistance, and a mesenchymal, stem-like phenotype. Mesenchymal-like GBMs were highly contractile and expressed elevated levels of glycoproteins that expanded their glycocalyx, and they were surrounded by a stiff extracellular matrix that potentiated integrin mechanosignalling. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignalling and a bulky glycocalyx, implying a causal link towards a mesenchymal, stem-like phenotype in GBMs. Strategies to ameliorate GBM tissue tension offer a therapeutic approach to reduce mortality due to GBM.
多形性胶质母细胞瘤（GBMs）是复发性致命性脑肿瘤。复发性 GBM 常表现出间质、干细胞样表型，这可以解释它们对治疗的耐药性。分析表明，复发性 GBM 张力增加，并表达高水平的糖蛋白，增加糖萼的体积。研究表明，体积庞大的糖萼增强了整合素机械信号转导和组织张力，并促进了 GBM 中的间质、干细胞样表型。增益和缺失功能研究表明，整合素机械信号转导是 GBM 生长、存活、侵袭和治疗耐药的诱导因素，也是间质、干细胞样表型的诱导因素。间充质样 GBM 具有高度的收缩性，并表达高水平的糖蛋白，使其糖萼扩张，它们被坚硬的细胞外基质包围，增强了整合素机械信号转导。我们的研究结果表明，整合素机械信号转导和庞大的糖萼之间存在动态和相互联系，暗示了 GBM 中向间质、干细胞样表型的因果关系。减轻 GBM 组织张力的策略为降低 GBM 死亡率提供了一种治疗方法。
