Abstract: Background – Metabolic adaptations fuel the outgrowth of tumor cells during cancer initiation and progression. Appendicular osteosarcoma (OS) is an aggressive bone tumor of mesenchymal origin in domestic dogs, presenting a naturally occurring model for translational studies.
Hypothesis/Objectives – Using a cross-species approach, central carbon metabolism was assessed in ten primary and metastatic canine and murine OS cell lines in comparison with mesenchymal stromal cells.
Methods – In vitro study using patient-derived and transgenic cell lines, grown under variable oxygen tension and biomimetic hydrogel environments. Metabolism measured using Seahorse respirometry, cell viability assays and mass spectrometry of glycolysis, citric acid cycle and pentose phosphate pathway metabolites.
Results – Metastatic canine and murine OS cells displayed a high degree of metabolic flexibility in the energetic state compared to primary cells. Hypoxia increased relative cell viability of canine and murine OS under selective availability of glucose, glutamine or pyruvate. Adjusting hydrogel matrix stiffness alone was sufficient to reprogram the metabolic signature of primary and metastatic OS cells, with evidence of differentially upregulated metabolites in nine cell lines under soft, lung-like hydrogel environments. L-lactate consumption directly contributed to mitochondrial oxidation in real-time, and inhibition of the malate-aspartate shuttle impaired lactate metabolism. Inhibition of lactate shuttling by monocarboxylate transporter (MCT)1/4 dual inhibition was superior to MCT1 inhibition alone in combination with carboplatin chemotherapy for reduction of OS cell viability.
Conclusions and clinical importance – These findings represent an investigation into the metabolic flexibility of OS and may hold future clinical implications in precision oncology.
