ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity
Cancer cells undergo morphological changes and phenotype switching to promote invasion into healthy tissues. Manipulating the transitional morphological states in cancer cells to prevent tumor dissemination may enhance survival and improve treatment response. We describe two members of the RhoGTPase activating protein (ARHGAP) family, ARHGAP12 and ARHGAP29, as regulators of transitional morphological states in glioma via Src kinase signaling events, leading to morphological changes that correspond to phenotype switching. Moreover, we establish a link between glycogen synthase kinase 3 (GSK-3) inhibition and β-catenin translocation in altering transcription of ARHGAP12 and ARHGAP29. Silencing ARHGAP12 causes loss of N-cadherin and adoption of mesenchymal morphology, a characteristic feature of aggressive cellular behavior. In patients with glioblastoma (GBM), we identify a link between ARHGAP12 and ARHGAP29 co-expression and recurrence after treatment. Consequently, we propose that further investigation of how ARHGAPs regulate transitional morphological events to drive cancer dissemination is warranted.
Authors
- Sean Lawler (ORCID: https://orcid.org/0000-0002-1633-2339)
- Katie Myers (ORCID: https://orcid.org/0000-0002-1951-4744)
- Sally Prior (ORCID: https://orcid.org/0009-0009-0985-7506)
- Malte Kriegs (ORCID: https://orcid.org/0000-0002-6195-8920)
- Michel Mittelbronn (ORCID: https://orcid.org/0000-0002-2998-052X)
- Mark Dunning (ORCID: https://orcid.org/0000-0002-8853-9435)
- Arndt Rohwedder
- Matt Humphries
- Sabine Knipp
- Georgia Mavria (ORCID: https://orcid.org/0000-0002-7227-1614)
- Sophie Ketchen
- Julia Cockle (ORCID: https://orcid.org/0000-0001-9437-4633)
- Ewan E. Morrison (ORCID: https://orcid.org/0000-0001-6269-6638)
- Vinton W.T. Cheng (ORCID: https://orcid.org/0000-0003-4159-8697)
- James Samarasekara
- John E. Ladbury (ORCID: https://orcid.org/0000-0002-6328-7200)
- Marjorie Boissinot (ORCID: https://orcid.org/0000-0002-5241-2520)
- Yun Wah Lam (ORCID: https://orcid.org/0000-0001-8929-5965)
- Ruth Morton
- Philippa Vaughn-Beaucaire (ORCID: https://orcid.org/0009-0000-7362-1869)
- Anke Brüning‐Richardson (ORCID: https://orcid.org/0000-0002-9862-9805)
- Gary Shaw (ORCID: https://orcid.org/0000-0001-9344-4433)
- Alastair Droop (ORCID: https://orcid.org/0000-0001-7695-7480)
- Ola Rominiyi (ORCID: https://orcid.org/0000-0002-9724-0224)
- Connor McGarrity-Cottrell
- Susan Short (ORCID: https://orcid.org/0000-0003-4423-7256)
- Josie Hayes (ORCID: https://orcid.org/0000-0001-6402-6320)
- Giorgos D. Michalopoulos (ORCID: https://orcid.org/0000-0002-7473-7262)
- Spencer J. Collis (ORCID: https://orcid.org/0000-0002-7874-1891)
- Azzam Ismail (ORCID: https://orcid.org/0000-0002-9019-6881)
- Sarah Fagan (ORCID: https://orcid.org/0000-0003-0366-6054)
- Daniel Tams
- Filomena Esteves
- George Psakis
Institutions
- Johannes Kepler University of Linz (AT)
- University of Leeds (GB)
- University of Huddersfield (GB)
- Institute of Cancer Research (GB)
- Universität Hamburg (DE)
- University of Luxembourg (LU)
- Brown University (US)
- Leeds Teaching Hospitals NHS Trust (GB)
- St James's University Hospital (GB)
- Revolution Medicines (United States) (US)
- Luxembourg Institute of Health (LU)
- University Medical Center Hamburg-Eppendorf (DE)
- Queen's Hospital (GB)
- University Cancer Center Hamburg (DE)
- Laboratoire National de Santé (LU)
- University of Birmingham (GB)
- Wellcome Trust (GB)
- University of Sheffield (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115361
- Citations
- 1
- Primary Topic
- Heat shock proteins research
- Type
- article
- Field-Weighted Citation Impact
- 0.81