Inhibition of ATR prevents macropinocytosis driven retraction of neurites and opposes invasion in GBM
Inhibition of ATR prevents macropinocytosis driven retraction of neurites and opposes invasion in GBM
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DOI：
10.21203/rs.3.rs-967109/v1
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发表时间：
2021-10
影响因子：
5.6
通讯作者：
J. Birch;K. Strathdee;Katrina Stevenson;S. Derby;L. Dutton;Emily Clough;Anna L. Koessinger;L. Gilmour;E. McGhee;Connor McGarrity-Cottrell;Aurelie anderlinden Dibekeme;S. Collis;Ola Rominiyi;Leandro Lembruber Soares;G. Solecki;F. Winkler;L. Carlin;G. Inman;A. Chalmers;J. Norman;R. Carruthers
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作者：
J. Birch;K. Strathdee;Katrina Stevenson;S. Derby;L. Dutton;Emily Clough;Anna L. Koessinger;L. Gilmour;E. McGhee;Connor McGarrity-Cottrell;Aurelie anderlinden Dibekeme;S. Collis;Ola Rominiyi;Leandro Lembruber Soares;G. Solecki;F. Winkler;L. Carlin;G. Inman;A. Chalmers;J. Norman;R. Carruthers
胶质母细胞瘤（GBM）是最常见和最具侵袭性的原发性脑肿瘤，尽管经过数十年的研究，仍然无法治愈。GBM的特征是高度浸润性生长模式，导致患者经历深刻的认知和神经症状，并导致治疗后不可避免的复发。减少健康大脑浸润的新疗法有可能改善临床症状并提高生存率。在这里，我们报告了一个新的作用，共济失调毛细血管扩张和拉德3相关激酶（ATR）在支持GBM细胞的侵袭性，通过调节巨胞饮驱动的整合素粘附受体的内化。我们证明，抑制ATR反对GBM迁移在体外，并相应地减少原位小鼠模型中的浸润行为。这些结果表明，ATR抑制，除了其作为放射增敏剂的用途，可能是有效的，在减少GBM浸润及其相关症状。
Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour and remains incurable despite decades of research. GBM are characterised by highly infiltrative growth patterns that contribute to the profound cognitive and neurological symptoms experienced by patients, and to inevitable recurrence following treatment. Novel treatments that reduce infiltration of the healthy brain have potential to ameliorate clinical symptoms and improve survival. Here, we report a novel role of the Ataxia telangiectasia and Rad 3 related kinase (ATR) in supporting the invasive properties of GBM cells through the regulation of macropinocytosis-driven internalisation of integrin adhesion receptors. We demonstrate that inhibition of ATR opposes GBM migration in vitro, and correspondingly reduces infiltrative behaviour in orthotopic mouse models. These results indicate that ATR inhibition, in addition to its use as a radiosensitiser, may be effective in reducing GBM infiltration and its associated symptoms.