A Drosophila RNAi screen reveals conserved glioblastoma-related adhesion genes that regulate collective cell migration

Abstract

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, 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 glioblastoma 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 glioblastoma and border cell migration thus may reveal conserved mechanisms that drive collective tumor cell invasion.

Transcriptome analysis reveals temporally regulated genetic networks duringDrosophilaborder cell collective migration

“…Similarly, border cells require complex regulation of cell-cell adhesions for their collective migration to maintain cluster integrity and shape as well as to migrate on and between nurse cells [20; 67; 19; 23; 6]. Recent genetic screens and targeted approaches have uncovered various adhesion genes, including septate junction genes, that promote border cell collective cohesion and migration [53; 70; 23]. Consistent with this, we observed a broad pattern of dynamic adhesion-related gene expression from early- to late-migration stages.…”

Relating the Biogenesis and Function of P Bodies in Drosophila to Human Disease

“…Combining the excellent genetic amenability with the conservation of key organ systems [143,144], Drosophila has a strong history in modelling a myriad of human diseases (see https://www.sdbonline.org/sites/fly/modelsystem/aamodelsystem.htm, accessed on 18 August 2023 for a comprehensive summary, or [145][146][147][148][149][150][151][152][153]). These attributes can also be applied to the study of pathogenesis caused by the dysregulation of RNP granules at a molecular, cellular, tissue, and organismal level.…”