Osteosarcoma (OSA) is a malignant mesenchymal tumour representing the most common bone neoplasia in both human and canine patients. In dogs, this tumour is characterised by a rapid growth and high metastatic rates. Despite significant improvements in surgical and chemotherapeutic treatments, most dogs perish within a year from the diagnosis, indicating a need for the identification of specific tumour targets to develop novel treatment strategies. Canine OSA shares key features with its human counterpart, such as clinical presentation, histopathological features, biological behaviour, and response to therapies, as well as molecular features including aberrant expression and mutation of driver genes. Furthermore, canine OSA is a spontaneously occurring tumour that accurately recapitulates human OSA tumour heterogeneity, microenvironment, and host immune response, with a 27 times higher incidence in dogs compared to humans. Over the last decade, Next-Generation Sequencing (NGS) technologies have provided crucial insights into the mechanisms driving the pathogenesis and progression of human OSA. In the last years, deep characterization of animal models by NGS has been gradually included as well, finding its main application in comparative oncology. Cancer cell lines are considered valuable models in basic cancer research, drug discovery, and translational medicine. Also, the recent profiling of a large panel of human cancer cell lines with omics technologies has empowered data-driven precision medicine. Despite the substantial number of studies in veterinary oncology, an analogous dataset modelling canine cancer cell lines is currently unavailable. The first goal of this PhD program was to provide a comprehensive molecular characterization of a number of canine OSA cell lines, by an integrative analysis of Whole-Exome Sequencing and RNA sequencing data, recapitulating in vivo canine OSA pathogenesis and allowing future investigations on the functional implications of their mutational and transcriptomic profiles. Given the relevant role of protein kinases in the development and growth of cancer cells, particular attention was given to the mutations affecting the kinome. The second aim of this project was to select a specific kinase inhibitor based on the mutational and transcriptomic profiling of these cell lines to evaluate its biological effects and cell line response to target therapy. The results of my PhD provide valuable insights into the molecular mechanisms of a large number of canine OSA cell lines. Furthermore, these data strongly confirm the role of the dog as a naturally occurring model for human OSA, and assess canine OSA cell lines as a valuable translational model to empower prospective in vitro studies both in humans and in dogs, allowing future investigations of their functional implications and drug response.
Gola, C., Giannuzzi, D., Rinaldi, A., Iussich, S., Modesto, P., Morello, E., Buracco, P., Aresu, L., De Maria, R. Genomic and Transcriptomic Characterization of Canine Osteosarcoma Cell Lines: A Valuable Resource in Translational Medicine. Front Vet Sci. 2021 May 17;8:666838.
Del Magno, S., Morello, E., Iussich, S., Gola, C., Dalpozzo, B., Annoni, M., Martano, M., Massari, F., Giacobino, D., Piras, LA., Stefanello, D., Buracco, P. Evaluation of the neoplastic infiltration of the skin overlying canine subcutaneous soft tissue sarcomas: An explorative study. Vet Comp Oncol. 2021 Jun;19(2):304-310.
Levi, M., Salaroli, R., Parenti, F., De Maria, R., Zannoni, A., Bernardini, C., Gola, C., Brocco, A., Marangio, A., Benazzi, C., Muscatello, LV., Brunetti, B., Forni, M., Sarli, G. Doxorubicin treatment modulates chemoresistance and affects the cell cycle in two canine mammary tumour cell lines. BMC Vet Res. 2021 Jan 18;17(1):30.
Gola, C., Iussich, S., Martano, M., Gattino, F., Morello, E., Martignani, E., Maniscalco, L., Accornero, P., Buracco, P., Aresu, L., De Maria, R. (2020) Clinical significance and in vitro cellular regulation of hypoxia mimicry on HIF-1α and downstream genes in canine appendicular osteosarcoma. The Veterinary Journal, 264:105538.
Nicoletti, A., Aresu, L., Marino, M., Massaro, M., Martignani, E., Caporali, E., Cappuccini, S., Bonfanti, U., Gola, C. (2020) CD3-CD20-positive nodal lymphoma with cross-lineage rearrangement. Journal of Veterinary Diagnostic Investigation, 32(6):964-967.
Sánchez-Céspedes, R., Accornero, P., Miretti, S., Martignani, E., Gattino, F., Maniscalco, L., Gola, C., Iussich, S., Martano, M., Morello, E., Buracco, P., Aresu, L., De Maria, R. (2020) In vitro and in vivo effects of toceranib phosphate in canine osteosarcoma cell lines and associated xenograft orthotopic model. Veterinary Comparative Oncology, 18(1), 117-127.
Gattino, F., Maniscalco, L., Iussich, S., Biasato, I., Martano, M., Morello, E., Gola, C., Millan, Y., Saeki N., Buracco, P., De Las Mulas, J., De Maria, R. (2018) PDGFR-α, PDGFR-β, VEGFR-2 and CD117 expression in canine mammary tumours and evaluation of the in vitro effects of toceranib phosphate in neoplastic mammary cell lines. The Veterinary Record, 183(7):221.