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Updated: Jan 18, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeting matrix metalloproteinase-14 disrupts DNA repair and reduces viability in adrenocortical carcinoma
Changxian Shen1, Liudmila V Popova1, Daniel M Chopyk1
1Division of Surgical Oncology, The Ohio State University and Arthur G. James Comprehensive Cancer Center; Columbus, Ohio, USA.
Background:
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer with limited treatment options and poor prognosis. Identifying novel therapeutic targets requires understanding the molecular drivers of ACC progression and establishing translational models for preclinical validation.
Results:
Matrix metalloproteinase-14 (MMP-14) is the most highly expressed MMP in ACC, and high MMP-14 expression is associated with worse overall and disease-free survival. We demonstrate that MMP-14 is essential for ACC cell survival and serves an unexpected role in maintaining genome stability. Genetic silencing or pharmacologic inhibition of MMP-14 significantly reduced viability in both NCI-H295R cells and patient-derived tumor organoids (PTOs). MMP-14 knockdown induced CHK1 activation and S-phase checkpoint arrest. Mechanistically, MMP-14 translocates to the nucleus and binds to chromatin following DNA damage induced by ionizing radiation or cisplatin. Loss of MMP-14 resulted in accumulation of DNA double-strand breaks, as evidenced by increased γH2AX foci, and impaired non-homologous end joining (NHEJ)-mediated repair.
Conclusions:
These findings reveal a novel nuclear function for MMP-14 in DNA repair and identify MMP-14 as a promising therapeutic target in ACC. Targeting MMP-14 may sensitize ACC tumors to DNA-damaging chemotherapy by impairing the repair of therapy-induced lesions.
Insights
Matrix metalloproteinase-14 (MMP-14) is crucial for adrenocortical carcinoma (ACC) cell survival and genome stability. Inhibiting MMP-14 shows promise as a therapeutic strategy for ACC by impairing DNA repair mechanisms.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with limited therapeutic options.
- Understanding ACC molecular drivers is key to identifying novel treatment targets.
- Translational models are essential for preclinical validation of potential therapies.
Purpose of the Study:
- To investigate the role of Matrix metalloproteinase-14 (MMP-14) in adrenocortical carcinoma (ACC) progression.
- To determine if MMP-14 is a viable therapeutic target for ACC.
Main Methods:
- Genetic silencing and pharmacologic inhibition of MMP-14 in ACC cell lines (NCI-H295R) and patient-derived tumor organoids (PTOs).
- Assessment of cell viability, DNA damage (γH2AX foci), and DNA repair pathways (non-homologous end joining - NHEJ).
- Analysis of MMP-14 localization within the cell nucleus following DNA damage.
Main Results:
- MMP-14 is highly expressed in ACC and associated with poorer patient survival.
- MMP-14 is essential for ACC cell survival, with its inhibition reducing viability.
- MMP-14 knockdown triggers DNA damage response pathways, including CHK1 activation and S-phase arrest.
- MMP-14 translocates to the nucleus, binds chromatin, and plays a role in repairing DNA double-strand breaks via NHEJ.
Conclusions:
- MMP-14 has a novel nuclear function in DNA repair, beyond its known extracellular roles.
- MMP-14 is identified as a promising therapeutic target for adrenocortical carcinoma.
- Targeting MMP-14 may enhance the efficacy of DNA-damaging chemotherapy in ACC by preventing the repair of induced DNA lesions.
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