Drosophila melanogaster as a Model System for Human Glioblastomas
Drosophila melanogaster as a Model System for Human Glioblastomas
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DOI：
10.1007/978-3-030-23629-8_12
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发表时间：
2019-01-01
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影响因子：
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通讯作者：
Read, Renee D.
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文献类型：
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作者：
Chen, Alexander S.;Read, Renee D.
多形性胶质母细胞瘤（GBM）是最常见的成人原发性恶性脑肿瘤。基因组扩增、激活突变以及受体酪氨酸激酶（RTK）如表皮生长因子受体（EGFR）的过表达，以及核心RTK信号转导通路中的基因如磷脂酰肌醇 -3激酶（PI3K）在GBM中很常见。然而，在临床上针对这些通路的努力大多没有成功，GBM患者的中位生存期仍然很差，为14 - 15个月。因此，为了改善患者的预后，必须齐心协力阐明GBM肿瘤发生所涉及的潜在生物学机制。由于黑腹果蝇相对于传统小鼠模型具有许多实验优势，它已成为促进我们对GBM肿瘤发生理解的一种非常有效的模型。例如，人类和果蝇之间存在广泛的细胞和遗传同源性，并且与人类疾病相关的基因中有75%具有功能性的果蝇直系同源基因。为了利用这些特性，我们开发了一种具有EGFR和PI3K组成性激活变体的果蝇GBM模型，该模型有效地重现了GBM疾病的关键方面。研究人员利用该模型进行正向遗传筛选，并扩展了其功能，在GBM肿瘤发生的关键成分需求方面有了许多重要发现，包括涉及细胞外基质信号传导、糖酵解代谢、侵袭/迁移、干细胞命运和分化以及不对称细胞分裂的基因和通路。果蝇将继续揭示参与胶质瘤发生的新的生物学通路和机制，并且这些知识可能有助于制定有效的治疗策略以改善患者的预后。
Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Genomic amplifications, activating mutations, and overexpression of receptor tyrosine kinases (RTKs) such as EGFR, and genes in core RTK signaling transduction pathways such as PI3K are common in GBM. However, efforts to target these pathways have been largely unsuccessful in the clinic, and the median survival of GBM patients remains poor at 14-15 months. Therefore, to improve patient outcomes, there must be a concerted effort to elucidate the underlying biology involved in GBM tumorigenesis. Drosophila melanogaster has been a highly effective model for furthering our understanding of GBM tumorigenesis due to a number of experimental advantages it has over traditional mouse models. For example, there exists extensive cellular and genetic homology between humans and Drosophila, and 75% of genes associated with human disease have functional fly orthologs. To take advantage of these traits, we developed a Drosophila GBM model with constitutively active variants of EGFR and PI3K that effectively recapitulated key aspects of GBM disease. Researchers have utilized this model in forward genetic screens and have expanded on its functionality to make a number of important discoveries regarding requirements for key components in GBM tumorigenesis, including genes and pathways involved in extracellular matrix signaling, glycolytic metabolism, invasion/migration, stem cell fate and differentiation, and asymmetric cell division. Drosophila will continue to reveal novel biological pathways and mechanisms involved in gliomagenesis, and this knowledge may contribute to the development of effective treatment strategies to improve patient outcomes.