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

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

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...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Vol. 10; no. 10; p. 2771
Main Authors: Ishibashi, Julien Roy, Keshri, Riya, Taslim, Tommy Henry, Brewer, Daniel Kennedy, Chan, Tung Ching, Lyons, Scott, McManamen, Anika Marie, Chen, Ashley, Del Castillo, Debra, Ruohola-Baker, Hannele
Format: Journal Article
Language:English
Published: Basel MDPI AG 16-10-2021
MDPI
Subjects:
Apoptosis
Breast cancer
cancer
Cancer therapies
Cell differentiation
Cell survival
Drosophila
Drug development
Drug dosages
Females
Food irradiation
Genetic screening
Genotoxicity
germline
Homeostasis
Insects
Males
NF-κB protein
Organoids
Prostate
quiescence
Radiation
Stem cells
Tumors
Yeast
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Summary: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.
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These authors contributed equally to this work.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells10102771