A Drosophila RNAi screen reveals conserved glioblastoma-related adhesion genes that regulate collective cell migration.
A Drosophila RNAi screen reveals conserved glioblastoma-related adhesion genes that regulate collective cell migration.
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DOI：
10.1093/g3journal/jkab356
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发表时间：
2022-01-04
期刊：
影响因子：
--
通讯作者：
McDonald JA
中科院分区：
文献类型：
--
作者：
Kotian N;Troike KM;Curran KN;Lathia JD;McDonald JA
迁移细胞群是胚胎发育的关键，但也有助于多种癌症的侵袭和转移。细胞群可以侵入组织深处，导致肿瘤进展和对治疗的抵抗。在致死性脑肿瘤胶质母细胞瘤（GBM）中也观察到集体细胞侵袭，它浸润周围的脑实质，导致肿瘤生长和患者预后不良。果蝇边界细胞作为一个小细胞簇在发育中的卵巢中迁移，是一个被充分研究和遗传可接近的模型，用于确定在天然组织环境中控制集体细胞迁移的一般机制。大多数细胞集体在通过组织和器官迁移过程中通过各种细胞-细胞粘附蛋白保持凝聚力。在这项研究中，我们首次发现了在人类脑肿瘤中表达的细胞粘附、细胞基质、细胞连接和相关调控基因。我们在边界细胞中对果蝇同源基因进行了RNAi敲除，以评估集群的迁移和/或凝聚力是否受到损害。从这个筛选中，我们确定了八个与粘附相关的基因，这些基因在RNAi敲低时破坏了边界细胞的集体迁移。生物信息学分析进一步表明，人类GBM患者肿瘤边缘和侵袭边缘的同源基因亚群升高。这些数据共同表明，在肿瘤侵袭中具有潜在作用的保守细胞粘附和粘附调节蛋白也可以调节细胞的集体迁移。因此，这种与GBM和边界细胞迁移相关的粘附基因的双重筛选方法可能揭示驱动肿瘤细胞集体侵袭的保守机制。
Migrating cell collectives are key to embryonic development but also contribute to invasion and metastasis of a variety of cancers. Cell collectives can invade deep into tissues, leading to tumor progression and resistance to therapies. Collective cell invasion is also observed in the lethal brain tumor glioblastoma (GBM), which infiltrates the surrounding brain parenchyma leading to tumor growth and poor patient outcomes. Drosophila border cells, which migrate as a small cell cluster in the developing ovary, are a well-studied and genetically accessible model used to identify general mechanisms that control collective cell migration within native tissue environments. Most cell collectives remain cohesive through a variety of cell–cell adhesion proteins during their migration through tissues and organs. In this study, we first identified cell adhesion, cell matrix, cell junction, and associated regulatory genes that are expressed in human brain tumors. We performed RNAi knockdown of the Drosophila orthologs in border cells to evaluate if migration and/or cohesion of the cluster was impaired. From this screen, we identified eight adhesion-related genes that disrupted border cell collective migration upon RNAi knockdown. Bioinformatics analyses further demonstrated that subsets of the orthologous genes were elevated in the margin and invasive edge of human GBM patient tumors. These data together show that conserved cell adhesion and adhesion regulatory proteins with potential roles in tumor invasion also modulate collective cell migration. This dual screening approach for adhesion genes linked to GBM and border cell migration thus may reveal conserved mechanisms that drive collective tumor cell invasion.
影响因子：
4
作者：
Stark K;Crowe O;Lewellyn L
通讯作者：
Lewellyn L