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Updated: Jun 4, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models
Daniele Boso1, Ilaria Piga2, Chiara Trento2
1Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Background:
Mitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted.
Methods:
Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels.
Results:
Genetic analysis revealed that mtDNA variants predicted as pathogenic, mainly involving complex I and IV genes, were present in all but one PDX (n = 20) at different levels of heteroplasmy, including 7 PDXs with homoplasmic variants. Functional analyses demonstrated that pathogenic mtDNA variants impacted on respiratory complexes activity and subunits abundance as well as on mitochondrial morphology. Moreover, PDX cells bearing homoplasmic mtDNA variants behaved as glucose-addicted and could barely survive glucose starvation in vitro. RNA-seq analysis indicated that mtDNA mutated (heteroplasmy > 50%) PDXs were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. These findings led us to investigate whether pathogenic mtDNA variants correlated with response to anti-VEGF therapy, since the latter was shown to reduce glucose availability in tumors. Strikingly, PDXs bearing homoplasmic pathogenic mtDNA variants associated with improved survival upon anti-VEGF treatment in mice, compared with mtDNA wild type or low heteroplasmy PDXs.
Conclusions:
These results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs.
Insights
Mitochondrial DNA variants in ovarian cancer influence cellular metabolism and drug response. Pathogenic variants, especially homoplasmic ones, predict better survival with anti-VEGF therapy, suggesting biomarker potential.
Area of Science:
- Oncology
- Genetics
- Cellular Metabolism
Background:
- Mitochondrial DNA (mtDNA) pathogenic variants are found in solid tumors like ovarian cancer (OC).
- These variants may cause mitochondrial dysfunction and alter cellular metabolism.
- Their role in cancer and drug response is not well understood.
Purpose of the Study:
- To characterize mtDNA variants in OC patient-derived xenografts (PDX).
- To investigate the functional impact of these variants on cancer cells.
- To explore the association between mtDNA variants and response to anti-VEGF therapy.
Main Methods:
- Genetic analysis of mtDNA variants in 20 OC PDXs.
- Functional assays assessing mitochondrial activity and morphology.
- RNA-sequencing to analyze metabolic pathways.
- Correlation analysis with anti-VEGF treatment response.
Main Results:
- Pathogenic mtDNA variants were common in OC PDXs, with some being homoplasmic.
- These variants affected respiratory complex activity, mitochondrial morphology, and glucose metabolism.
- PDX cells with homoplasmic variants showed increased glycolysis and were glucose-dependent.
- PDXs with homoplasmic pathogenic mtDNA variants showed improved survival with anti-VEGF therapy.
Conclusions:
- mtDNA variants are linked to altered cancer cell metabolism.
- Homoplasmic pathogenic mtDNA variants may serve as biomarkers for anti-angiogenic drug response in ovarian cancer.
