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

Vinton Cheng; Philippa Vaughn-Beaucaire; Gary C. Shaw; Malte Kriegs; Alastair Droop; George Psakis; Michel  Mittelbronn; Matthew Humphries; Filomena O. Gamboa-Esteves; Josie Hayes; Julia V. Cockle; Sabine Knipp; Arndt Rohwedder; Azzam Ismail; Ola Rominiyi; Spencer Collis; Georgia Mavria; James Samarasekara; John E. Ladbury; Sophie E. Ketchen; Ruth Morton; Sarah Fagan; Daniel Tams; Katie Myers; Connor McGarrity-Cottrell; Mark Dunning; Marjorie Boissinot; George Michalopoulos; Sally Prior; Yun Wah Lam; Ewan E. Morrison; Susan C. Short; Sean Lawler; Anke Bruning-Richardson

doi:10.1016/j.celrep.2025.115361

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

Vinton Cheng, Philippa Vaughn-Beaucaire, Gary C. Shaw, Malte Kriegs, Alastair Droop, George Psakis, Michel Mittelbronn, Matthew Humphries, Filomena O. Gamboa-Esteves, Josie Hayes, Julia V. Cockle, Sabine Knipp, Arndt Rohwedder, Azzam Ismail, Ola Rominiyi, Spencer Collis, Georgia Mavria, James Samarasekara, John E. Ladbury, Sophie E. KetchenRuth Morton, Sarah Fagan, Daniel Tams, Katie Myers, Connor McGarrity-Cottrell, Mark Dunning, Marjorie Boissinot, George Michalopoulos, Sally Prior, Yun Wah Lam, Ewan E. Morrison, Susan C. Short, Sean Lawler, Anke Bruning-Richardson

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Article number	115361
Number of pages	25
Journal	Cell Reports
Volume	44
Issue number	3
Early online date	6 Mar 2025
DOIs	https://doi.org/10.1016/j.celrep.2025.115361
Publication status	E-pub ahead of print - 6 Mar 2025

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10.1016/j.celrep.2025.115361Licence: CC BY

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Cheng, V., Vaughn-Beaucaire, P., Shaw, G. C., Kriegs, M., Droop, A., Psakis, G., Mittelbronn, M., Humphries, M., Gamboa-Esteves, F. O., Hayes, J., Cockle, J. V., Knipp, S., Rohwedder, A., Ismail, A., Rominiyi, O., Collis, S., Mavria, G., Samarasekara, J., Ladbury, J. E., ... Bruning-Richardson, A. (2025). ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity. Cell Reports, 44(3), [115361]. https://doi.org/10.1016/j.celrep.2025.115361

@article{b1cedd6a51d443b8a2049a963b481c24,

title = "ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity",

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 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.",

keywords = "glioma, RhoGTPase activating protein, glycogen synthase kinase 3, cell morphology, Src kinase signaling, tumor recurrence, BIO-indirubin, Cancer",

author = "Vinton Cheng and Philippa Vaughn-Beaucaire and Shaw, {Gary C.} and Malte Kriegs and Alastair Droop and George Psakis and Michel Mittelbronn and Matthew Humphries and Gamboa-Esteves, {Filomena O.} and Josie Hayes and Cockle, {Julia V.} and Sabine Knipp and Arndt Rohwedder and Azzam Ismail and Ola Rominiyi and Spencer Collis and Georgia Mavria and James Samarasekara and Ladbury, {John E.} and Ketchen, {Sophie E.} and Ruth Morton and Sarah Fagan and Daniel Tams and Katie Myers and Connor McGarrity-Cottrell and Mark Dunning and Marjorie Boissinot and George Michalopoulos and Sally Prior and Lam, {Yun Wah} and Morrison, {Ewan E.} and Short, {Susan C.} and Sean Lawler and Anke Bruning-Richardson",

note = "Funding Information: We would like to dedicate this study to Pamela Roberts, the late Charity Director of the PPR Foundation, and to her late husband Peter, who passed away from a brain tumor. This study was financially supported by the PPR Foundation. The Cloudbuster-associated work was funded by the IBIN network. M.M. would like to thank the Luxembourg National Research Fund (FNR) for grant support (FNR PEARL P16/BM/11192868). The University of Huddersfield ICF Funds, United Kingdom, also financially contributed to this work. We would like to thank Dr Teklu Egnui for technical assistance. Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = mar,

day = "6",

doi = "10.1016/j.celrep.2025.115361",

language = "English",

volume = "44",

journal = "Cell Reports",

issn = "2639-1856",

publisher = "Cell Press",

number = "3",

}

Cheng, V, Vaughn-Beaucaire, P, Shaw, GC, Kriegs, M, Droop, A, Psakis, G, Mittelbronn, M, Humphries, M, Gamboa-Esteves, FO, Hayes, J, Cockle, JV, Knipp, S, Rohwedder, A, Ismail, A, Rominiyi, O, Collis, S, Mavria, G, Samarasekara, J, Ladbury, JE, Ketchen, SE, 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, S & Bruning-Richardson, A 2025, 'ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity', Cell Reports, vol. 44, no. 3, 115361. https://doi.org/10.1016/j.celrep.2025.115361

TY - JOUR

T1 - ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity

AU - Cheng, Vinton

AU - Vaughn-Beaucaire, Philippa

AU - Shaw, Gary C.

AU - Kriegs, Malte

AU - Droop, Alastair

AU - Psakis, George

AU - Mittelbronn, Michel

AU - Humphries, Matthew

AU - Gamboa-Esteves, Filomena O.

AU - Hayes, Josie

AU - Cockle, Julia V.

AU - Knipp, Sabine

AU - Rohwedder, Arndt

AU - Ismail, Azzam

AU - Rominiyi, Ola

AU - Collis, Spencer

AU - Mavria, Georgia

AU - Samarasekara, James

AU - Ladbury, John E.

AU - Ketchen, Sophie E.

AU - Morton, Ruth

AU - Fagan, Sarah

AU - Tams, Daniel

AU - Myers, Katie

AU - McGarrity-Cottrell, Connor

AU - Dunning, Mark

AU - Boissinot, Marjorie

AU - Michalopoulos, George

AU - Prior, Sally

AU - Lam, Yun Wah

AU - Morrison, Ewan E.

AU - Short, Susan C.

AU - Lawler, Sean

AU - Bruning-Richardson, Anke

N1 - Funding Information: We would like to dedicate this study to Pamela Roberts, the late Charity Director of the PPR Foundation, and to her late husband Peter, who passed away from a brain tumor. This study was financially supported by the PPR Foundation. The Cloudbuster-associated work was funded by the IBIN network. M.M. would like to thank the Luxembourg National Research Fund (FNR) for grant support (FNR PEARL P16/BM/11192868). The University of Huddersfield ICF Funds, United Kingdom, also financially contributed to this work. We would like to thank Dr Teklu Egnui for technical assistance. Publisher Copyright: © 2025

PY - 2025/3/6

Y1 - 2025/3/6

N2 - 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.

AB - 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.

KW - glioma

KW - RhoGTPase activating protein

KW - glycogen synthase kinase 3

KW - cell morphology

KW - Src kinase signaling

KW - tumor recurrence

KW - BIO-indirubin

KW - Cancer

UR - http://www.scopus.com/inward/record.url?scp=85219673443&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2025.115361

DO - 10.1016/j.celrep.2025.115361

M3 - Article

VL - 44

JO - Cell Reports

JF - Cell Reports

SN - 2639-1856

IS - 3

M1 - 115361

ER -

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

Abstract

UN SDGs

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Mind the GAP(s) – How to Halt Brain Tumour Invasion

Sean Lawler

Brown University

Integrated Biological Imaging Network (External organisation)

Cite this

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

Abstract

UN SDGs

Access to Document

Other files and links

Activities

Mind the GAP(s) – How to Halt Brain Tumour Invasion

Sean Lawler

Brown University

Integrated Biological Imaging Network (External organisation)

Cite this