Department of Mathematics, Konkuk University, Seoul 05029, Republic of Korea.
Mathematical Biosciences Institute, Ohio State University, Columbus, OH 43210, USA.
Philos Trans R Soc Lond B Biol Sci. 2020 Sep 14;375(1807):20190390. doi: 10.1098/rstb.2019.0390. Epub 2020 Jul 27.
Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with a short median survival time. GBM is characterized by the hallmarks of aggressive proliferation and cellular infiltration of normal brain tissue. miR-451 and its downstream molecules are known to play a pivotal role in regulation of the balance of proliferation and aggressive invasion in response to metabolic stress in the tumour microenvironment (TME). Surgery-induced transition in reactive astrocyte populations can play a significant role in tumour dynamics. In this work, we develop a multi-scale mathematical model of miR-451-LKB1-AMPK-OCT1-mTOR pathway signalling and individual cell dynamics of the tumour and reactive astrocytes after surgery. We show how the effects of fluctuating glucose on tumour cells need to be reprogrammed by taking into account the recent history of glucose variations and an AMPK/miR-451 reciprocal feedback loop. The model shows how variations in glucose availability significantly affect the activity of signalling molecules and, in turn, lead to critical cell migration. The model also predicts that microsurgery of a primary tumour induces phenotypical changes in reactive astrocytes and stem cell-like astrocytes promoting tumour cell proliferation and migration by Cxcl5. Finally, we investigated a new anti-tumour strategy by Cxcl5-targeting drugs. This article is part of the theme issue 'Multi-scale analysis and modelling of collective migration in biological systems'.
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑癌，中位生存时间很短。GBM 的特征是具有侵袭性增殖和正常脑组织细胞浸润的特征标志。miR-451 及其下游分子在调节肿瘤微环境（TME）代谢应激下的增殖和侵袭侵袭平衡方面起着关键作用。手术诱导的反应性星形胶质细胞群体的转变可以在肿瘤动力学中发挥重要作用。在这项工作中，我们开发了 miR-451-LKB1-AMPK-OCT1-mTOR 通路信号转导和肿瘤及反应性星形胶质细胞个体细胞动力学的多尺度数学模型。我们展示了如何通过考虑葡萄糖波动的近期历史和 AMPK/miR-451 相互反馈回路，重新编程肿瘤细胞中波动的葡萄糖对肿瘤细胞的影响。该模型展示了葡萄糖供应的变化如何显著影响信号分子的活性，并反过来导致关键的细胞迁移。该模型还预测，原发性肿瘤的微创手术会诱导反应性星形胶质细胞和干细胞样星形胶质细胞发生表型变化，通过 CXCL5 促进肿瘤细胞增殖和迁移。最后，我们通过 CXCL5 靶向药物研究了一种新的抗肿瘤策略。本文是主题为“生物系统中集体迁移的多尺度分析和建模”的一部分。
