ABSTRACT
Cancer stem cells (CSCs) may be responsible for tumour dormancy, relapse and the eventual death of most cancer patients. In addition, these cells are usually resistant to cytotoxic conditions. However, very little is known about the biology behind this resistance to therapeutics. Here we investigated stem-cell death in the digestive system of adult Drosophila melanogaster. We found that knockdown of the coat protein complex I (COPI)-Arf79F (also known as Arf1) complex selectively killed normal and transformed stem cells through necrosis, by attenuating the lipolysis pathway, but spared differentiated cells. The dying stem cells were engulfed by neighbouring differentiated cells through a draper-myoblast city-Rac1-basket (also known as JNK)-dependent autophagy pathway. Furthermore, Arf1 inhibitors reduced CSCs in human cancer cell lines. Thus, normal or cancer stem cells may rely primarily on lipid reserves for energy, in such a way that blocking lipolysis starves them to death. This finding may lead to new therapies that could help to eliminate CSCs in human cancers.
Subject(s)
Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Drosophila melanogaster/cytology , Drosophila melanogaster/metabolism , Lipolysis/physiology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , ADP-Ribosylation Factor 1/antagonists & inhibitors , ADP-Ribosylation Factor 1/deficiency , Animals , Apoptosis , Autophagy , Cell Differentiation , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Cell Transformation, Neoplastic/drug effects , Coat Protein Complex I/deficiency , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drug Resistance, Neoplasm/drug effects , Energy Metabolism , Enterocytes/cytology , Female , Gastrointestinal Tract/pathology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Lipolysis/drug effects , MAP Kinase Signaling System , Male , Membrane Proteins/metabolism , Necrosis/chemically induced , Neoplastic Stem Cells/drug effects , Phagocytosis , rac GTP-Binding Proteins/metabolismABSTRACT
Stem cells are regulated both intrinsically and externally, including by signals from the local environment and distant organs. To identify genes and pathways that regulate stem-cell fates in the whole organism, we perform a genome-wide transgenic RNAi screen through ubiquitous gene knockdowns, focusing on regulators of adult Drosophila testis germline stem cells (GSCs). Here we identify 530 genes that regulate GSC maintenance and differentiation. Of these, we further knock down 113 selected genes using cell-type-specific Gal4s and find that more than half were external regulators, that is, from the local microenvironment or more distal sources. Some genes, for example, versatile (vers), encoding a heterochromatin protein, regulates GSC fates differentially in different cell types and through multiple pathways. We also find that mitosis/cytokinesis proteins are especially important for male GSC maintenance. Our findings provide valuable insights and resources for studying stem cell regulation at the organismal level.