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Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

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Listed:
  • Naoya Hirata

    (National Institute of Health Sciences)

  • Shigeru Yamada

    (National Institute of Health Sciences)

  • Takuji Shoda

    (National Institute of Health Sciences)

  • Masaaki Kurihara

    (National Institute of Health Sciences)

  • Yuko Sekino

    (National Institute of Health Sciences)

  • Yasunari Kanda

    (National Institute of Health Sciences)

Abstract

Many tumours originate from cancer stem cells (CSCs), which is a small population of cells that display stem cell properties. However, the molecular mechanisms that regulate CSC frequency remain poorly understood. Here, using microarray screening in aldehyde dehydrogenase (ALDH)-positive CSC model, we identify a fundamental role for a lipid mediator sphingosine-1-phosphate (S1P) in CSC expansion. Stimulation with S1P enhances ALDH-positive CSCs via S1P receptor 3 (S1PR3) and subsequent Notch activation. CSCs overexpressing sphingosine kinase 1 (SphK1), an S1P-producing enzyme, show increased ability to develop tumours in nude mice, compared with parent cells or CSCs. Tumorigenicity of CSCs overexpressing SphK1 is inhibited by S1PR3 knockdown or S1PR3 antagonist. Breast cancer patient-derived mammospheres contain SphK1+/ALDH1+ cells or S1PR3+/ALDH1+ cells. Our findings provide new insights into the lipid-mediated regulation of CSCs via Notch signalling, and rationale for targeting S1PR3 in cancer.

Suggested Citation

  • Naoya Hirata & Shigeru Yamada & Takuji Shoda & Masaaki Kurihara & Yuko Sekino & Yasunari Kanda, 2014. "Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5806
    DOI: 10.1038/ncomms5806
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    Cited by:

    1. Mingming Wu & Xiao Zhang & Weijie Zhang & Yi Shiou Chiou & Wenchang Qian & Xiangtian Liu & Min Zhang & Hong Yan & Shilan Li & Tao Li & Xinghua Han & Pengxu Qian & Suling Liu & Yueyin Pan & Peter E. Lo, 2022. "Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yujin Harada & Mayumi Yamada & Itaru Imayoshi & Ryoichiro Kageyama & Yutaka Suzuki & Takaaki Kuniya & Shohei Furutachi & Daichi Kawaguchi & Yukiko Gotoh, 2021. "Cell cycle arrest determines adult neural stem cell ontogeny by an embryonic Notch-nonoscillatory Hey1 module," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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