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An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism

Author

Listed:
  • Marisa Nacke

    (University of Glasgow
    The CRUK Beatson Institute)

  • Emma Sandilands

    (University of Glasgow
    The CRUK Beatson Institute)

  • Konstantina Nikolatou

    (University of Glasgow
    The CRUK Beatson Institute)

  • Álvaro Román-Fernández

    (University of Glasgow
    The CRUK Beatson Institute)

  • Susan Mason

    (The CRUK Beatson Institute)

  • Rachana Patel

    (The CRUK Beatson Institute)

  • Sergio Lilla

    (The CRUK Beatson Institute)

  • Tamas Yelland

    (The CRUK Beatson Institute)

  • Laura C. A. Galbraith

    (The CRUK Beatson Institute)

  • Eva C. Freckmann

    (University of Glasgow
    The CRUK Beatson Institute)

  • Lynn McGarry

    (The CRUK Beatson Institute)

  • Jennifer P. Morton

    (University of Glasgow
    The CRUK Beatson Institute)

  • Emma Shanks

    (The CRUK Beatson Institute)

  • Hing Y. Leung

    (University of Glasgow
    The CRUK Beatson Institute)

  • Elke Markert

    (The CRUK Beatson Institute)

  • Shehab Ismail

    (University of Glasgow
    The CRUK Beatson Institute
    KU Leuven)

  • Sara Zanivan

    (University of Glasgow
    The CRUK Beatson Institute)

  • Karen Blyth

    (University of Glasgow
    The CRUK Beatson Institute)

  • David M. Bryant

    (University of Glasgow
    The CRUK Beatson Institute)

Abstract

The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.

Suggested Citation

  • Marisa Nacke & Emma Sandilands & Konstantina Nikolatou & Álvaro Román-Fernández & Susan Mason & Rachana Patel & Sergio Lilla & Tamas Yelland & Laura C. A. Galbraith & Eva C. Freckmann & Lynn McGarry &, 2021. "An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21847-4
    DOI: 10.1038/s41467-021-21847-4
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    Cited by:

    1. Eva C. Freckmann & Emma Sandilands & Erin Cumming & Matthew Neilson & Alvaro Román-Fernández & Konstantina Nikolatou & Marisa Nacke & Tamsin R. M. Lannagan & Ann Hedley & David Strachan & Mark Salji &, 2022. "Traject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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