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Updated: Apr 12, 2026
Cancer-Associated Fibroblasts from Mouse Mammary Tumors as Tools for Molecular and Computational Studies
Published on: July 3, 2025
MMP3-mediated tumor progression is controlled transcriptionally by a novel IRF8-MMP3 interaction
Debarati Banik1, Colleen S Netherby1, Paul N Bogner2
1Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Abstract:
Interferon regulatory factor-8 (IRF8), originally identified as a leukemic tumor suppressor, can also exert anti-neoplastic activities in solid tumors. We previously showed that IRF8-loss enhanced tumor growth, which was accompanied by reduced tumor-cell susceptibility to apoptosis. However, the impact of IRF8 expression on tumor growth could not be explained solely by its effects on regulating apoptotic response. Exploratory gene expression profiling further revealed an inverse relationship between IRF8 and MMP3 expression, implying additional intrinsic mechanisms by which IRF8 modulated neoplastic behavior. Although MMP3 expression was originally linked to tumor initiation, the role of MMP3 beyond this stage has remained unclear. Therefore, we hypothesized that MMP3 governed later stages of disease, including progression to metastasis, and did so through a novel IRF8-MMP3 axis. Altogether, we showed an inverse mechanistic relationship between IRF8 and MMP3 expression in tumor progression. Importantly, the growth advantage due to IRF8-loss was significantly compromised after silencing MMP3 expression. Moreover, MMP3-loss reduced spontaneous lung metastasis in an orthotopic mouse model of mammary carcinoma. MMP3 acted, in part, in a cell-intrinsic manner and served as a direct transcriptional target of IRF8. Thus, we identified a novel role of an IRF8-MMP3 axis in tumor progression, which unveils new therapeutic opportunities.
Insights
Interferon regulatory factor-8 (IRF8) suppresses tumor growth and metastasis by inhibiting matrix metalloproteinase-3 (MMP3). Loss of IRF8 promotes cancer progression, but targeting MMP3 offers new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Interferon regulatory factor-8 (IRF8) exhibits tumor suppressor activity in solid tumors.
- Previous studies linked IRF8 loss to enhanced tumor growth and reduced apoptosis.
- The role of matrix metalloproteinase-3 (MMP3) in later stages of tumor progression remained unclear.
Purpose of the Study:
- To investigate the novel IRF8-MMP3 axis in tumor progression and metastasis.
- To determine if MMP3 contributes to tumor growth and metastasis beyond tumor initiation.
- To explore therapeutic opportunities targeting the IRF8-MMP3 interaction.
Main Methods:
- Gene expression profiling to identify relationships between IRF8 and MMP3.
- Experimental manipulation of IRF8 and MMP3 expression in cancer cells.
- Assessment of tumor growth and lung metastasis in an orthotopic mouse model.
- Analysis of MMP3 as a transcriptional target of IRF8.
Main Results:
- An inverse relationship was confirmed between IRF8 and MMP3 expression during tumor progression.
- Silencing MMP3 significantly reduced the tumor growth advantage observed with IRF8 loss.
- MMP3 loss decreased spontaneous lung metastasis in a mammary carcinoma model.
- MMP3 was identified as a direct transcriptional target of IRF8, acting partly in a cell-intrinsic manner.
Conclusions:
- A novel IRF8-MMP3 axis plays a critical role in regulating tumor progression and metastasis.
- IRF8 suppresses tumor growth and metastasis by transcriptionally inhibiting MMP3.
- This axis presents a potential new therapeutic target for cancer treatment.
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