Tep1 Regulates Yki Activity in Neural Stem Cells in Drosophila Glioma Model
Tep1 Regulates Yki Activity in Neural Stem Cells in Drosophila Glioma Model
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DOI：
10.3389/fcell.2020.00306
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发表时间：
2020-05-08
影响因子：
5.5
通讯作者：
Kango-Singh, Madhuri
中科院分区：
文献类型：
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作者：
Gangwani, Karishma;Snigdha, Kirti;Kango-Singh, Madhuri
多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，预后较差。表皮生长因子受体（EGFR）的扩增和导致磷脂酰肌醇-3激酶（PI3K）途径激活的突变通常与GBM相关。利用先前发表的一个由神经胶质细胞中PI3K和EGFR通路共激活产生的果蝇胶质瘤模型[通过下调Pten和致癌Ras的过表达]，我们发现果蝇Tep1基因（人类CD109的同源基因）通过一种进化保守的机制调节Yki（人类YAP/TAZ的同源基因）。在临床相关模型中，YAP/TAZ通路的致癌信号发生在细胞获得CD109以响应辐射诱导的炎症环境中。此外，Tep1的下调导致Yki活性降低和胶质瘤生长减少。Yki在幼体中枢神经系统中的一个关键功能是干细胞更新和成神经细胞的形成。其他报告表明，在视叶和幼虫中枢神经系统的中枢脑区，Yki活动的上游调节因子不同。我们假设Tep1与Hippo通路效应因子Yki相互作用以调节神经母细胞数量。我们测试了Tep1是否通过Yki影响胶质瘤的生长，以及在正常细胞中Tep1是否影响神经母细胞的数量和增殖。我们的数据表明，Tep1影响神经胶质瘤中Yki介导的干细胞更新，因为Tep的降低显著减少了神经胶质瘤中神经母细胞的数量。因此，我们确定了Tep1-Yki在幼体中枢神经系统中的相互作用，在胶质瘤的生长和进展中起关键作用。
Glioblastoma Multiforme (GBM) is the most common form of malignant brain tumor with poor prognosis. Amplification of Epidermal Growth Factor Receptor (EGFR), and mutations leading to activation of Phosphatidyl-Inositol-3 Kinase (PI3K) pathway are commonly associated with GBM. Using a previously published Drosophila glioma model generated by coactivation of PI3K and EGFR pathways [by downregulation of Pten and overexpression of oncogenic Ras] in glial cells, we showed that the Drosophila Tep1 gene (ortholog of human CD109) regulates Yki (the Drosophila ortholog of human YAP/TAZ) via an evolutionarily conserved mechanism. Oncogenic signaling by the YAP/TAZ pathway occurs in cells that acquire CD109 expression in response to the inflammatory environment induced by radiation in clinically relevant models. Further, downregulation of Tep1 caused a reduction in Yki activity and reduced glioma growth. A key function of Yki in larval CNS is stem cell renewal and formation of neuroblasts. Other reports suggest different upstream regulators of Yki activity in the optic lobe versus the central brain regions of the larval CNS. We hypothesized that Tep1 interacts with the Hippo pathway effector Yki to regulate neuroblast numbers. We tested if Tep1 acts through Yki to affect glioma growth, and if in normal cells Tep1 affects neuroblast number and proliferation. Our data suggests that Tep1 affects Yki mediated stem cell renewal in glioma, as reduction of Tep significantly decreases the number of neuroblasts in glioma. Thus, we identify Tep1-Yki interaction in the larval CNS that plays a key role in glioma growth and progression.