尽管在胶质母细胞瘤 (GBM) 中测试了多种分子靶向疗法，但在过去 20 年中，除了与护理标准放化疗相关的 TTfield 设置外，整个 GBM 患者群体的患者生存率并未取得显着进展。治疗抵抗与肿瘤之间和肿瘤微环境中的靶表达异质性和可塑性相关。我们重点关注临床前和临床样本中与侵袭性 GBM 相关的 α5 整合素。为了解决 α5 整合素异质性的特征，我们从患者数据开始，表明其 mRNA 水平升高与缺氧途径有关。我们开启了神经胶质瘤干细胞，这些细胞被认为处于肿瘤形成和复发的顶峰，但也因为它们位于缺氧环境中。我们证明α5整合素的表达是干细胞系依赖性的，并且在体外受到缺氧的正向调节。重要的是，表达的异质性在体内干细胞衍生的小鼠异种移植物中是保守的。在缺氧环境中，HIF-2α优先参与α5整合素表达，从而赋予GBM干细胞迁移能力。因此，HIF-2α和α5整合素抑制剂的组合导致α5整合素表达细胞的增殖和迁移受损。然而，HIF-2α 的稳定不足以控制整合素 α5 的表达。我们的结果表明，AHR（芳烃受体）表达与 HIF-2α 和 α5 整合素表达呈负相关，表明这两种转录因子之间存在功能竞争。总的来说，数据证实了 GBM 治疗靶标的高度异质性、HIF-2α 在缺氧环境中的诱导作用，并提出了一种攻击分子定义的 GBM 干细胞的新方法。版权所有 © 2024。由 Elsevier B.V. 出版。

Despite numerous molecular targeted therapies tested in glioblastoma (GBM), no significant progress in patient survival has been achieved in the last 20 years in the overall population of GBM patients except with TTfield setup associated with the standard of care chemoradiotherapy. Therapy resistance is associated with target expression heterogeneity and plasticity between tumors and in tumor niches. We focused on α5 integrin implicated in aggressive GBM in preclinical and clinical samples. To address the characteristics of α5 integrin heterogeneity we started with patient data indicating that elevated levels of its mRNA are related to hypoxia pathways. We turned on glioma stem cells which are considered at the apex of tumor formation and recurrence but also as they localize in hypoxic niches. We demonstrated that α5 integrin expression is stem cell line dependent and is modulated positively by hypoxia in vitro. Importantly, heterogeneity of expression is conserved in in vivo stem cell-derived mice xenografts. In hypoxic niches, HIF-2α is preferentially implicated in α5 integrin expression which confers migratory capacity to GBM stem cells. Hence combining HIF-2α and α5 integrin inhibitors resulted in proliferation and migration impairment of α5 integrin expressing cells. Stabilization of HIF-2α is however not sufficient to control integrin α5 expression. Our results show that AHR (aryl hydrocarbon receptor) expression is inversely related to HIF-2α and α5 integrin expressions suggesting a functional competition between the two transcription factors. Collectively, data confirm the high heterogeneity of a GBM therapeutic target, its induction in hypoxic niches by HIF-2α and suggest a new way to attack molecularly defined GBM stem cells.Copyright © 2024. Published by Elsevier B.V.