Mitochondrial DNA mutations are associated with response to anti-VEGF therapy in ovarian cancer PDX models

Mitochondrial DNA (mtDNA) mutations 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. In this study, we characterized mtDNA mutations in ovarian cancer patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels. To correlate the presence of mtDNA mutations and metabolic pathways that were modulated at the transcriptional level, RNA-seq analysis was performed in ascites-derived cells from 19 OC PDX (here named PDOVCA). Results indicated that mtDNA mutated (>50% VAF) PDX were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. Functional analysis demonstrated that mtDNA mutations modulated mitochondria activity, assembly capacity and morphology of mitochondrial complexes in PDX cells. Moreover, PDX cells bearing homoplasmic mtDNA mutations behave as glucose addicted and could barely survive glucose starvation in vitro. These findings led us to investigate whether mtDNA mutations correlated with response to anti-VEGF therapy, which was shown to reduce glucose availability in tumors. Strikingly, PDX bearing homoplasmic pathogenic mtDNA mutations had improved survival upon anti-VEGF treatment in mouse models, compared with PDX lacking mtDNA mutations or bearing them at low frequency. These results hint at mtDNA mutations as new biomarkers of response to antiangiogenic drugs. Ovarian cancer patient-derived xenografts were developed as previosuly described (Indraccolo S. et al., Eur J Cancer, 2006) and propagated by injecting tumor cells intra-peritoneally into 8-week-old female NOD/SCID mice. The ascitic component developed by 19 PDX was harvested and 1 million cells was collected for RNAseq analysis. We performed gene expression profiling analysis using data obtained from RNA-seq of 19 different PDOVCA ascites-derived cells Comparative gene expression profiling analysis of RNA-seq data between mtDNA mutated (VAF>50%) and wild type PDOVCA (VAF<50%)