Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534514/ https://www.ncbi.nlm.nih.gov/pubmed/34685753 http://dx.doi.org/10.3390/cells10102771 |
_version_ | 1784587571243778048 |
---|---|
author | 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 |
author_facet | 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 |
author_sort | Ishibashi, Julien Roy |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8534514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85345142021-10-23 Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis 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 Cells Article 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. MDPI 2021-10-16 /pmc/articles/PMC8534514/ /pubmed/34685753 http://dx.doi.org/10.3390/cells10102771 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis |
title | Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis |
title_full | Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis |
title_fullStr | Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis |
title_full_unstemmed | Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis |
title_short | Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis |
title_sort | chemical genetic screen in drosophila germline uncovers small molecule drugs that sensitize stem cells to insult-induced apoptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534514/ https://www.ncbi.nlm.nih.gov/pubmed/34685753 http://dx.doi.org/10.3390/cells10102771 |
work_keys_str_mv | AT ishibashijulienroy chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT keshririya chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT taslimtommyhenry chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT brewerdanielkennedy chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT chantungching chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT lyonsscott chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT mcmanamenanikamarie chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT chenashley chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT delcastillodebra chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis AT ruoholabakerhannele chemicalgeneticscreenindrosophilagermlineuncoverssmallmoleculedrugsthatsensitizestemcellstoinsultinducedapoptosis |