A novel model of osteosarcomagenesis reveals dysregulation of oxidative phosphorylation

The purpose of this study is to develop a new model to study osteosarcoma in order to elucidate cellular pathways important in osteosarcomagenesis that are potential therapeutic targets. Osteosarcoma is the most common bone malignancy in childhood and early adolescence. Thirty percent of patients with the rare genetic disorder Type II Rothmund-Thomson syndrome (RTS) develop osteosarcoma. Patients with RTS have biallelic mutations in the RECQL4 gene, which encodes an ATP-dependent DNA helicase. Unfortunately, many attempts to model RTS-associated osteosarcoma have not been successful. Here, we describe a patient-derived induced pluripotent stem cell (iPSC) model capable of recapitulating the process of osteosarcomagenesis. Briefly, RTS patient fibroblasts are reprogrammed to iPSCs, then subsequently differentiated to mesenchymal stem cells. These cells are validated and further differentiated to early and late osteoblasts, the potential precursors of osteosarcoma. Because the iPSC-derived osteoblasts retain the genetic fidelity of the patient from which they were derived, we believe these cells are the ideal model to study the molecular mechanism associated with RTS-associated osteosarcoma. Utilizing the patient-derived osteoblasts, we have performed RNAseq and subsequent GSEA analyses to explore the transcriptome of RTS osteoblasts and found the dysregulation of oxidative phosphorylation in RTS osteoblasts. Interestingly, it has been reported that specific vacuolar ATPases are upregulated in patient cells. It has been reported that vacuolar ATPases function to increase proton concentration within the mitochondria and also within the extracellular environment. Understanding key mechanisms of osteosarcomagenesis is critical to making steps toward novel therapeutics. Citation Format: Brittany E. Jewell, An Xu, Ruoji Zhou, Dandan Zhu, Linchao Lu, Ruying Zhao, Lisa L. Wang, Dung-Fang Lee. A novel model of osteosarcomagenesis reveals dysregulation of oxidative phosphorylation [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B36.