An ILK/STAT3 pathway controls glioblastoma stem cell plasticity

Alexander E.P Loftus; Marianna S. Romano; Anh Nguyen Phuong; Ben J McKinnel; Morwenna T Muir; Muhammad Furqan; John C Dawson; Lidia Avalle; Adam T Douglas; Richard L. Mort; Adam Byron; Neil O Carragher; Steven M Pollard; Valerie G Brunton; Margaret C Frame

doi:10.1016/j.devcel.2024.09.003

An ILK/STAT3 pathway controls glioblastoma stem cell plasticity

Alexander E.P Loftus^*, Marianna S. Romano, Anh Nguyen Phuong, Ben J McKinnel, Morwenna T Muir, Muhammad Furqan, John C Dawson, Lidia Avalle, Adam T Douglas, Richard L. Mort, Adam Byron, Neil O Carragher, Steven M Pollard, Valerie G Brunton, Margaret C Frame

^*Corresponding author for this work

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

Abstract

Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumour progression and therapeutic resistance. Here we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) is a key determinant of phenotypic plasticity, mesenchymal-like morphology and invasive behaviour in a mouse GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss gives rise to cells that are unable to respond to multiple cell state transition cues. We further show that a ROCK-regulated ILK/STAT3 signalling pathway mediates the plasticity that enables transition of GBM stem cells to an astrocyte-like state in vitro and in vivo. Finally, we find that ILK expression correlates with expression of STAT3-regulated proteins and protein signatures that describe astrocyte-like and mesenchymal cells in patient tumours. This work establishes the adhesion protein ILK as a pivotal regulator of multiple malignancy-associated GBM phenotypes including phenotypic plasticity and mesenchymal state

Original language	English
Journal	Developmental Cell
DOIs	https://doi.org/10.1016/j.devcel.2024.09.003
Publication status	Published - 25 Sept 2024

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10.1016/j.devcel.2024.09.003

PIIS1534580724005318
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 7.28 MBLicence: CC BY

Systems approach to therapeutic combinations for glioblastoma: new targets and agents delivered and sequenced for synergy
Carragher, N. (Principal Investigator) & Frame, M. (Co-investigator)
UK-based charities
1/09/19 → 31/08/24
Project: Research
Expoiting adhesion protein networks in glioblastoma
Frame, M. (Principal Investigator), Brunton, V. (Co-investigator), Byron, A. (Co-investigator) & Pollard, S. (Co-investigator)
UK-based charities
1/05/18 → 30/04/23
Project: Research

Edinburgh Drug Discovery
Unciti-Broceta, A. (Manager), Webster, S. (Manager) & Carragher, N. (Manager)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

@article{c50ff7c1568243639071aaa61c54f1df,

title = "An ILK/STAT3 pathway controls glioblastoma stem cell plasticity",

abstract = "Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumour progression and therapeutic resistance. Here we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) is a key determinant of phenotypic plasticity, mesenchymal-like morphology and invasive behaviour in a mouse GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss gives rise to cells that are unable to respond to multiple cell state transition cues. We further show that a ROCK-regulated ILK/STAT3 signalling pathway mediates the plasticity that enables transition of GBM stem cells to an astrocyte-like state in vitro and in vivo. Finally, we find that ILK expression correlates with expression of STAT3-regulated proteins and protein signatures that describe astrocyte-like and mesenchymal cells in patient tumours. This work establishes the adhesion protein ILK as a pivotal regulator of multiple malignancy-associated GBM phenotypes including phenotypic plasticity and mesenchymal state",

author = "Loftus, {Alexander E.P} and Romano, {Marianna S.} and Phuong, {Anh Nguyen} and {J McKinnel}, Ben and Muir, {Morwenna T} and Muhammad Furqan and Dawson, {John C} and Lidia Avalle and Douglas, {Adam T} and {L. Mort}, Richard and Adam Byron and Carragher, {Neil O} and Pollard, {Steven M} and Brunton, {Valerie G} and Frame, {Margaret C}",

year = "2024",

month = sep,

day = "25",

doi = "10.1016/j.devcel.2024.09.003",

language = "English",

journal = "Developmental Cell",

issn = "1534-5807",

publisher = "Cell Press",

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T1 - An ILK/STAT3 pathway controls glioblastoma stem cell plasticity

AU - Loftus, Alexander E.P

AU - Romano, Marianna S.

AU - Phuong, Anh Nguyen

AU - J McKinnel, Ben

AU - Muir, Morwenna T

AU - Furqan, Muhammad

AU - Dawson, John C

AU - Avalle, Lidia

AU - Douglas, Adam T

AU - L. Mort, Richard

AU - Byron, Adam

AU - Carragher, Neil O

AU - Pollard, Steven M

AU - Brunton, Valerie G

AU - Frame, Margaret C

PY - 2024/9/25

Y1 - 2024/9/25

N2 - Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumour progression and therapeutic resistance. Here we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) is a key determinant of phenotypic plasticity, mesenchymal-like morphology and invasive behaviour in a mouse GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss gives rise to cells that are unable to respond to multiple cell state transition cues. We further show that a ROCK-regulated ILK/STAT3 signalling pathway mediates the plasticity that enables transition of GBM stem cells to an astrocyte-like state in vitro and in vivo. Finally, we find that ILK expression correlates with expression of STAT3-regulated proteins and protein signatures that describe astrocyte-like and mesenchymal cells in patient tumours. This work establishes the adhesion protein ILK as a pivotal regulator of multiple malignancy-associated GBM phenotypes including phenotypic plasticity and mesenchymal state

AB - Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumour progression and therapeutic resistance. Here we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) is a key determinant of phenotypic plasticity, mesenchymal-like morphology and invasive behaviour in a mouse GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss gives rise to cells that are unable to respond to multiple cell state transition cues. We further show that a ROCK-regulated ILK/STAT3 signalling pathway mediates the plasticity that enables transition of GBM stem cells to an astrocyte-like state in vitro and in vivo. Finally, we find that ILK expression correlates with expression of STAT3-regulated proteins and protein signatures that describe astrocyte-like and mesenchymal cells in patient tumours. This work establishes the adhesion protein ILK as a pivotal regulator of multiple malignancy-associated GBM phenotypes including phenotypic plasticity and mesenchymal state

U2 - 10.1016/j.devcel.2024.09.003

DO - 10.1016/j.devcel.2024.09.003

M3 - Article

SN - 1534-5807

JO - Developmental Cell

JF - Developmental Cell

ER -

An ILK/STAT3 pathway controls glioblastoma stem cell plasticity

Abstract

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Projects

Systems approach to therapeutic combinations for glioblastoma: new targets and agents delivered and sequenced for synergy

Expoiting adhesion protein networks in glioblastoma

Equipment

Edinburgh Drug Discovery

Cite this