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

Julien Roy Ishibashi,Riya Keshri,Ashley Chen,Daniel Kennedy Brewer,Tung Ching Chan,Anika Marie Mcmanamen,Hannele Ruohola-Baker,Scott Lyons,Tommy Henry Taslim,Debra Del Castillo

doi:10.3390/cells10102771

Abstract

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.

Highlights

In adult organisms, stem cells maintain organ homeostasis by differentiating into diverse specialized cells and through the property of self-renewal
Cancer-initiating cells/cancer stem cells (CSCs) are a subpopulation of cancer cells with the unique ability to avoid apoptosis, produce diverse progeny, and metastasize
We report novel bioactivities of several small molecule drug candidates with high therapeutic potential for cancer treatment

Summary

Introduction

Stem cells maintain organ homeostasis by differentiating into diverse specialized cells and through the property of self-renewal. Tumorinitiating cells, known as cancer stem cells (CSCs), contribute to tumor homeostasis by producing heterogeneous cancer cells in a solid tumor. Both adult stem cells and CSCs show resistance to chemical- or radiation-induced apoptosis and can enter “quiescence”, a reversible state of proliferative arrest. There’s an emerging need to develop targeted therapies that eradicate CSCs by preventing quiescence and/or promoting apoptosis Several pharmacological drugs such as salinomycin (affects proliferation), LGK974 (affects Wnt pathway), and MK-0752 (affects Notch pathway) are under clinical trial for ablation of the CSCs [2,3,4]. Decrypting normal adult stem cells survival and quiescence after insult may help identify druggable pathways utilized by cancer stem cells

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