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Updated: Aug 22, 2025
A Mouse Model to Investigate the Role of Cancer-Associated Fibroblasts in Tumor Growth
Published on: December 22, 2020
ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome
Massimiliano Mellone1, Klaudia Piotrowska1, Giulia Venturi1
1School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Abstract:
Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti-PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance.
Significance:
ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors.
Insights
Ataxia-telangiectasia mutated (ATM) signaling drives myofibroblastic cancer-associated fibroblast (myoCAF) accumulation, hindering anti-tumor immunity. Targeting ATM may reverse myoCAF differentiation, enhancing T-cell infiltration and immunotherapy response in difficult-to-treat tumors.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Myofibroblastic cancer-associated fibroblasts (myoCAFs) are linked to poor patient outcomes in solid tumors.
- myoCAF-rich tumors exhibit limited T-cell infiltration and resistance to immune-checkpoint blockade.
- The molecular drivers of myoCAF accumulation and their impact on anti-tumor immunity are not fully understood.
Purpose of the Study:
- To identify key regulators of myoCAF differentiation.
- To investigate the role of ATM signaling in myoCAF phenotype.
- To explore therapeutic strategies targeting ATM for enhancing cancer immunotherapy.
Main Methods:
- In vitro differentiation of myofibroblasts and ex vivo culture of myoCAFs.
- Genetic and pharmacological inhibition of ATM signaling.
- Assessment of ATM activation via NOX4, DNA damage, and oxidative stress.
- In vivo studies in myoCAF-rich tumor models.
Main Results:
- Activated ATM signaling was identified in differentiating myofibroblasts and myoCAFs.
- Targeting ATM suppressed and reversed myoCAF differentiation.
- NOX4-mediated oxidative stress and DNA damage regulated ATM activation.
- In vivo ATM inhibition reduced tumor growth, increased CD8 T-cell infiltration, and improved immunotherapy efficacy.
Conclusions:
- ATM is a central regulator of myoCAF differentiation and phenotype.
- Targeting ATM offers a potential strategy to overcome CAF-mediated immunotherapy resistance.
- ATM inhibitors combined with checkpoint blockade may benefit patients with myoCAF-rich, immune-cold tumors.
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