Boso Daniele, Piga Ilaria, Trento Chiara, Minuzzo Sonia, Angi Eleonora, Iommarini Luisa, Lazzarini Elisabetta, Caporali Leonardo, Fiorini Claudio, D'Angelo Luigi, De Luise Monica, Kurelac Ivana, Fassan Matteo, Porcelli Anna Maria, Navaglia Filippo, Billato Ilaria, Esposito Giovanni, Gasparre Giuseppe, Romualdi Chiara, Indraccolo Stefano
Basic and Translational Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Gattamelata, 64 - 35128, Padua, Italy.
J Exp Clin Cancer Res. 2024 Dec 19;43(1):325. doi: 10.1186/s13046-024-03239-w.
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.
Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels.
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.
These results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs.
线粒体DNA（mtDNA）致病变体已在包括卵巢癌（OC）在内的多种实体瘤中被报道，卵巢癌是最致命的妇科恶性肿瘤，由于其可能诱导线粒体功能障碍和细胞代谢重编程而引起了人们的关注。尽管近年来取得了进展，但癌症中mtDNA变体的功能特征及其对药物反应的可能调节在很大程度上仍未明确。
在此，我们对源自卵巢癌患者的异种移植瘤（PDX）中的mtDNA变体进行了表征，并在多个水平上研究了它们对癌细胞的影响。
遗传分析显示，预测为致病的mtDNA变体主要涉及复合体I和IV基因，除一个PDX（n = 20）外，所有PDX中均存在不同水平的异质性，包括7个具有纯质性变体的PDX。功能分析表明，致病的mtDNA变体影响呼吸复合体活性和亚基丰度以及线粒体形态。此外，携带纯质性mtDNA变体的PDX细胞表现出对葡萄糖的成瘾性，并且在体外几乎无法在葡萄糖饥饿条件下存活。RNA测序分析表明，mtDNA发生突变（异质性> 50%）的PDX具有上调的糖酵解和其他与癌症代谢相关的途径。这些发现促使我们研究致病的mtDNA变体是否与抗VEGF治疗的反应相关，因为后者已被证明可降低肿瘤中的葡萄糖可用性。令人惊讶的是，与mtDNA野生型或低异质性PDX相比，携带与小鼠抗VEGF治疗后生存率提高相关的纯质性致病mtDNA变体的PDX。
这些结果表明mtDNA变体可能是抗血管生成药物反应的潜在生物标志物。
