Nikolatou, K. et al. (2023) PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer. EMBO Journal, 42, e1139. (doi: 10.15252/embj.2023113987) (PMID:37577760) (PMCID:PMC10505920)
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Abstract
Dysregulation of the PI3K/AKT pathway is a common occurrence in high-grade serous ovarian carcinoma (HGSOC), with the loss of the tumour suppressor PTEN in HGSOC being associated with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We here utilise time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency induces PI(3,4,5)P3-rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability of HGSOC cells upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor β1-integrin (ITGB1) as key ARF6 interactors in HGSOC regulating PTEN loss-associated invasion. ARF6 functions to promote invasion by controlling the recycling of internalised, active β1-integrin to maintain invasive activity into the ECM. The expression of the CYTH2-ARF6-AGAP1 complex in HGSOC patients is inversely associated with outcome, allowing the identification of patient groups with improved versus poor outcome. ARF6 may represent a therapeutic vulnerability in PTEN-depleted HGSOC.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by the following grants: D.M.B. NIH K99CA163535, CRUK (C596/A19481) E.S., AR.-F., D. S. and L. McG., CRUK C596/A17196 and A31287. K.N. was supported by a Cancer Research UK Glasgow Centre PhD studentship (C7932/A25170). E.M.C. was supported by a University of Glasgow MVLS Doctoral Training Programme PhD Studentship. E.C.F. was supported by an industrial PhD studentship from Essen Bioscience and the University of Glasgow. S.Z and S.L were supported by CRUK (A29800 to S.Z.). L.B. and D.T.H, were supported by CRUK core funding to D.T.H. (A23278). M.N. R.S. and C.M were supported by CRUK core funding to C.M. (A29801). I.A.M. was supported by the Rivkin Center for Ovarian Cancer Research (574546) and Ovarian Cancer Action (P76567). J.C.N. was supported by CRUK Core funding (A28291). |
| Keywords: | Ovarian cancer, 3D spheroids, PTEN, ARF6, integrins. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Strachan, Mr David and Zanivan, Professor Sara and Freckmann, Eva and Miller, Professor Crispin and Norman, Professor James and Cumming, Erin and Roman-Fernandez, Dr Alvaro and Lilla, Dr Sergio and McGarry, Ms Lynn and Bryant, Dr David and Sandilands, Dr Emma and Mcneish, Professor Iain and Neilson, Dr Matthew and Nikolatou, Miss Konstantina and Huang, Professor Danny and Buetow, Dr Lori |
| Creator Roles: | Bryant, D.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft, Writing – review and editing Nikolatou, K.Data curation, Formal analysis, Validation, Investigation, Visualization, Writing – original draft, Writing – review and editing Sandilands, E.Data curation, Formal analysis, Validation, Investigation, Visualization, Writing – original draft, Writing – review and editing Roman-Fernandez, A.Data curation, Formal analysis, Validation, Investigation, Visualization Norman, J.Data curation, Formal analysis, Validation, Investigation, Methodology, Visualization Freckmann, E.Formal analysis, Methodology, Software, Visualization Lilla, S.Formal analysis, Validation, Investigation, Methodology McGarry, L.Formal analysis, Validation, Investigation Buetow, L.Validation, Investigation Cumming, E.Investigation Mcneish, I.Methodology, Resources Zanivan, S.Methodology, Supervision Neilson, M.Software Strachan, D.Software Miller, C.Supervision Huang, D.Supervision |
| Authors: | Nikolatou, K., Sandilands, E., Román-Fernández, A., Cumming, E. M., Freckmann, E., Lilla, S., Buetow, L., McGarry, L., Neilson, M., Shaw, R., Strachan, D., Miller, C., Huang, D. T., Mcneish, I. A., Norman, J. C., Zanivan, S., and Bryant, D. M. |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Research Group: | M22 |
| Journal Name: | EMBO Journal |
| Publisher: | Wiley |
| ISSN: | 0261-4189 |
| ISSN (Online): | 1460-2075 |
| Published Online: | 14 August 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in EMBO Journal 42:e1139 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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