ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity.

Cheng, VWT.; Vaughn-Beaucaire, P.; Shaw, GC.; Kriegs, M.; Droop, A.; Psakis, G.; Mittelbronn, M.; Humphries, M.; Esteves, F.; Hayes, J.; Cockle, JV.; Knipp, S.; Rohwedder, A.; Ismail, A.; Rominiyi, O.; Collis, SJ.; Mavria, G.; Samarasekara, J.; Ladbury, JE.; Ketchen, S.; Morton, R.; Fagan, S.; Tams, D.; Myers, K.; McGarrity-Cottrell, C.; Dunning, M.; Boissinot, M.; Michalopoulos, G.; Prior, S.; Lam, YW.; Morrison, EE.; Short, SC.; Lawler, SE.; Bruning-Richardson, A.

ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity.

All Authors

Cheng, VWT.

Vaughn-Beaucaire, P.

Shaw, GC.

Kriegs, M.

Droop, A.

Psakis, G.

Mittelbronn, M.

Humphries, M.

Esteves, F.

Hayes, J.

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LTHT Author

Humphries, Matthew
Ismail, Azzam

LTHT Department

Pathology
National Pathology Imaging Cooperative
Histopathology

Non Medic

Digital Pathology Systems Lead

Publication Date

2025

Item Type

Journal Article

Abstract

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 beta-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.