The use of a multi-metric readout screen to identify EHMT2/G9a-inhibition as a modulator of cancer-associated fibroblast activation state.

Autor: Wu NC; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada., Quevedo R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada., Nurse M; Department of Chemical Engineering & Applied Chemistry, University of Toronto, Toronto, ON, Canada., Hezaveh K; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada., Liu H; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada; Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada., Sun F; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada., Muffat J; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada., Sun Y; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada., Simmons CA; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada; Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, Canada., McGaha TL; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada., Prinos P; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., Arrowsmith CH; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Ailles L; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., D'Arcangelo E; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada. Electronic address: elisa.darcangelo@roche.com., McGuigan AP; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Chemical Engineering & Applied Chemistry, University of Toronto, Toronto, ON, Canada. Electronic address: alison.mcguigan@utoronto.ca.
Jazyk: angličtina
Zdroj: Biomaterials [Biomaterials] 2025 Mar; Vol. 314, pp. 122879. Date of Electronic Publication: 2024 Oct 05.
DOI: 10.1016/j.biomaterials.2024.122879
Abstrakt: Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression, including mediating tumour cell invasion via their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM). Given that reduced CAF abundance in tumours correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in regions of tumour-stromal mixing with the goal of reducing tumour aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, we performed an image-based, phenotypic screen that enabled us to identify modulators of CAF abundance and the capacity of CAFs to induce tumour cell invasion. We identified EHMT2 (also known as G9a), an enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as a potent modulator of CAF abundance and CAF-mediated tumour cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed EHMT2 participated in driving CAFs towards a pro-invasive phenotype and mediated CAF hyperproliferation, a feature typically associated with activated fibroblasts in tumours. Our study suggests that EHMT2 regulates CAF state within the tumour microenvironment by impacting CAF activation, as well as by magnifying the pro-invasive effects of these activated CAFs on tumour cell invasion through promoting CAF hyperproliferation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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