Spatial enrichment of phosphoinositide metabolism is a molecular switch to promote metastasis

Abstract

The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. We developed 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that select IQSEC1 variants, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by spatially restricting cortical 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 restrict cortical PI(3,4,5)P3 production to discrete domains, resulting in formation of invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion and metastasis in vitro and in vivo. IQSEC1-ARF expression predicts long-term outcome in prostate cancer patients. Spatial restriction of 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 represents a therapeutic vulnerability to stop metastasis. Highlights• Spatial restriction of PI(3,4,5)P3 is a molecular switch to promote invasion.• IQSEC1 is a GEF for ARF5/6, promoting PIP5K-dependent PI(3,4,5)P3 production downstream of the HGF receptor Met.• Pro-invasive IQSEC1 variants restrict cortical PI(3,4,5)P3 production to select cortical subdomains that convert into invasive protrusions.• IQSEC1 inhibition attenuates in vitro invasion and metastasis in vivo.• IQSEC1 module expression predicts disease-free survival in prostate cancer.