Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis

Cells

卷:10

Debra Del Castillo¹  Scott Lyons¹  Anika Marie McManamen¹  Julien Roy Ishibashi¹  Riya Keshri¹  Hannele Ruohola-Baker¹  Tommy Henry Taslim¹  Tung Ching Chan¹  Ashley Chen¹  Daniel Kennedy Brewer¹ 

[1] Department of Biochemistry, University of Washington, Seattle, WA 98195, USA;

关键词: Drosophila;    germline;    stem cells;    apoptosis;    cancer;    quiescence;   

DOI  :  10.3390/cells10102771

来源: DOAJ

【 摘 要 】

Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the Drosophila gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the Drosophila stem cell niche as a model system for targeted drug discovery.

【 授权许可】

Unknown