The small GTPase ARF3 controls invasion modality and metastasis by regulating N-cadherin levels

Sandilands, E. et al. (2023) The small GTPase ARF3 controls invasion modality and metastasis by regulating N-cadherin levels. Journal of Cell Biology, 222(4), e202206115. (doi: 10.1083/jcb.202206115) (PMID:36880595) (PMCID:PMC9997661)

Abstract

ARF GTPases are central regulators of membrane trafficking that control local membrane identity and remodeling facilitating vesicle formation. Unraveling their function is complicated by the overlapping association of ARFs with guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and numerous interactors. Through a functional genomic screen of three-dimensional (3D) prostate cancer cell behavior, we explore the contribution of ARF GTPases, GEFs, GAPs, and interactors to collective invasion. This revealed that ARF3 GTPase regulates the modality of invasion, acting as a switch between leader cell-led chains of invasion or collective sheet movement. Functionally, the ability of ARF3 to control invasion modality is dependent on association and subsequent control of turnover of N-cadherin. In vivo, ARF3 levels acted as a rheostat for metastasis from intraprostatic tumor transplants and ARF3/N-cadherin expression can be used to identify prostate cancer patients with metastatic, poor-outcome disease. Our analysis defines a unique function for the ARF3 GTPase in controlling how cells collectively organize during invasion and metastasis.

• Item Type: Articles
• Additional Information: This work was supported by the following grants: D.M. Bryant National Institutes of Health K99CA163535, CRUK (C596/ A19481). E. Sandilands, A. Roman-Fern ´ andez, and L. McGarry ´ CRUK C596A17196 and A31287. E.C. Freckmann was supported by a University of Glasgow Industrial Partnership PhD scheme co-funded by Essen Bioscience, Sartorius Group. E.M. Cumming was supported by a University of Glasgow MVLS Doctoral Training Programme PhD Studentship. R. Patel and H.L. Leung funded by CRUK (A22904). S. Mason, J. Anand, L. Galbraith, and K. Blyth CRUK (A29799, A17196, and A31287).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nixon, Mr Colin and McGarry, Ms Lynn and Bryant, Dr David and Roman Fernandez, Mr Alvaro and Blyth, Professor Karen and Leung, Professor Hing and Sandilands, Dr Emma and Freckmann, Eva and Mason, Miss Susan and Patel, Dr Rachana and Galbraith, Dr Laura and Cumming, Erin
• Authors: Sandilands, E., Freckmann, E. C., Cumming, E. M., Román-Fernández, A., McGarry, L., Anand, J., Galbraith, L., Mason, S., Patel, R., Nixon, C., Cartwright, J., Leung, H. Y., Blyth, K., and Bryant, D. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Cell Biology
• Publisher: Rockefeller University Press
• ISSN: 0021-9525
• ISSN (Online): 1540-8140
• Published Online: 28 February 2023
• Copyright Holders: Copyright © 2023 Sandilands et al.
• First Published: First published in Journal of Cell Biology 222(4): e202206115
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
170678		Non-Clinical Training Award Cycle 2	Owen Sansom	Cancer Research UK (CRUK)	C596/A19481	CS - Beatson Institute for Cancer Research