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

Nacke, M. et al. (2021) An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism. Nature Communications, 12, 1623. (doi: 10.1038/s41467-021-21847-4) (PMID:33712589) (PMCID:PMC7955138)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Roman-Fernandez, Dr Alvaro and Blyth, Professor Karen and Leung, Professor Hing and Freckmann, Eva and Nacke, Marisa and Shanks, Dr Emma and Lilla, Dr Sergio and Markert, Dr Elke and Zanivan, Professor Sara and Patel, Dr Rachana and Ismail, Dr Shehab and McGarry, Ms Lynn and Bryant, Dr David and Sandilands, Dr Emma and Morton, Professor Jen and Nikolatou, Konstantina and Mason, Miss Susan and Galbraith, Dr Laura
• Authors: Nacke, M., Sandilands, E., Nikolatou, K., Román-Fernández, Á., Mason, S., Patel, R., Lilla, S., Yelland, T., Galbraith, L. C.A., Freckmann, E. C., McGarry, L., Morton, J. P., Shanks, E., Leung, H. Y., Markert, E., Ismail, S., Zanivan, S., Blyth, K., and Bryant, D. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 1623
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
170638		Non-Clinical Training Award Cycle 2	David Bryant	Cancer Research UK (CRUK)	C596/A19481	Institute of Cancer Sciences
174115		CRUK Centre Renewal	Owen Sansom	Cancer Research UK (CRUK)	C7932/A25142	CS - Beatson Institute for Cancer Research