Letter | Published:

The lipolysis pathway sustains normal and transformed stem cells in adult Drosophila

Nature volume 538, pages 109113 (06 October 2016) | Download Citation

Abstract

Cancer stem cells (CSCs) may be responsible for tumour dormancy, relapse and the eventual death of most cancer patients1. 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.

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Acknowledgements

We thank S. Hayashi, J.-P. Vincent, M. Fortini, C. Thummel, E. Baehrecke, R. P. Kuhnlein, M. Freeman, F. Schweisguth, M. Mlodzik, T. Lecuit, DGRC, VDRC, and the Bloomington Stock Centers for fly stocks; A. Chavanieu and L. Frigerio for Arf1 inhibitors; X. Yang and the Developmental Studies Hybridoma Bank for antibodies; and S. Lockett for help with the confocal microscope. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

Author information

Author notes

    • Shree Ram Singh
    •  & Xiankun Zeng

    These authors contributed equally to this work.

Affiliations

  1. The Basic Research Laboratory, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA

    • Shree Ram Singh
    • , Xiankun Zeng
    • , Jiangsha Zhao
    • , Ying Liu
    • , Gerald Hou
    • , Hanhan Liu
    •  & Steven X. Hou

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  2. Search for Xiankun Zeng in:

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Contributions

S.X.H., X.Z. and S.R.S. conceived and designed the experiments. S.R.S., X.Z. and S.X.H. performed the Drosophila experiments. J.Z. performed the experiments using human cancer cell lines. Y.L., G.H. and H.L. assisted with experiments. S.X.H., S.R.S., X.Z. and J.Z. analysed the data. S.X.H., S.R.S. and J.Z. wrote the manuscript. S.X.H. and S.R.S. revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Steven X. Hou.

Reviewer Information

Nature thanks Y. Apidianakis, M. Montminy, H. Steller and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Videos

  1. 1.

    A dying ISC is engulfed by a neighbouring EC

    The genotype esgts>Arf79FRNAi - guts were stained with antibodies to Arm (red), GFP (green) and DAPI (blue).

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https://doi.org/10.1038/nature19788

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