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

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, Jennifer P. Morton, Emma Shanks, Hing Y. Leung, Elke Markert, Shehab Ismail, Sara Zanivan, Karen Blyth and David M. Bryant ()
Additional contact information
Marisa Nacke: University of Glasgow
Emma Sandilands: University of Glasgow
Konstantina Nikolatou: University of Glasgow
Álvaro Román-Fernández: University of Glasgow
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
Lynn McGarry: The CRUK Beatson Institute
Jennifer P. Morton: University of Glasgow
Emma Shanks: The CRUK Beatson Institute
Hing Y. Leung: University of Glasgow
Elke Markert: The CRUK Beatson Institute
Shehab Ismail: University of Glasgow
Sara Zanivan: University of Glasgow
Karen Blyth: University of Glasgow
David M. Bryant: University of Glasgow

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21847-4

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