Abstract
Osteosarcoma (OSA) represents the most common primary bone tumor in dogs and is characterized by a highly aggressive behavior. Cell lines represent one of the most suitable and reproducible pre-clinical models, and therefore the knowledge of their molecular landscape is mandatory to investigate oncogenic mechanisms and drug response. The present study aims at determining variants, putative driver genes, and gene expression aberrations by integrating whole-exome and RNA sequencing. For this purpose, eight canine OSA cell lines and one matched pair of primary tumor and normal tissue were analyzed. Overall, cell lines revealed a mean tumor mutational burden of 9.6 mutations/Mb (range 3.9–16.8). Several known oncogenes and tumor suppressor genes, such as ALK, MYC, and MET, were prioritized as having a likely role in canine OSA. Mutations in eight genes, previously described as human OSA drivers and including TP53, PTCH1, MED12, and PI3KCA, were retrieved in our cell lines. When variants were cross-referenced with human OSA driver mutations, the E273K mutation of TP53 was identified in the Wall cell line and tumor sample. The transcriptome profiling detected two possible p53 inactivation mechanisms in the Wall cell line on the one hand, and in D17 and D22 on the other. Moreover, MET overexpression, potentially leading to MAPK/ERK pathway activation, was observed in D17 and D22 cell lines. In conclusion, our data provide the molecular characterization of a large number of canine OSA cell lines, allowing future investigations on potential therapeutic targets and associated biomarkers. Notably, the Wall cell line represents a valuable model to empower prospective in vitro studies both in human and in dogs, since the TP53 driver mutation was maintained during cell line establishment and was widely reported as a mutation hotspot in several human cancers.
Highlights
IntroductionCanine osteosarcoma (cOSA) represents the most common primary malignant bone tumor in dogs [1, 2] and is characterized by a natural history of disease and molecular abnormalities similar to human osteosarcoma (hOSA) [3, 4]. cOSA is locally aggressive and highly metastatic [5], and despite significant improvements of surgical and chemotherapeutic treatments, most dogs perishNGS of Canine Osteosarcoma Cell Lines within a year from the diagnosis [6], indicating a need for identification of specific tumor targets to develop novel treatment strategies
Canine osteosarcoma represents the most common primary malignant bone tumor in dogs [1, 2] and is characterized by a natural history of disease and molecular abnormalities similar to human osteosarcoma [3, 4]. cOSA is locally aggressive and highly metastatic [5], and despite significant improvements of surgical and chemotherapeutic treatments, most dogs perishNGS of Canine Osteosarcoma Cell Lines within a year from the diagnosis [6], indicating a need for identification of specific tumor targets to develop novel treatment strategies
Driver mutations in MAPK/ERK and PI3K/AKT signaling pathways were identified in cOSA cell lines, and an anti-proliferative target inhibition using trametinib showed encouraging results, while alterations of the TP53 pathway were detected in non-sensitive cell lines [13]
Summary
Canine osteosarcoma (cOSA) represents the most common primary malignant bone tumor in dogs [1, 2] and is characterized by a natural history of disease and molecular abnormalities similar to human osteosarcoma (hOSA) [3, 4]. cOSA is locally aggressive and highly metastatic [5], and despite significant improvements of surgical and chemotherapeutic treatments, most dogs perishNGS of Canine Osteosarcoma Cell Lines within a year from the diagnosis [6], indicating a need for identification of specific tumor targets to develop novel treatment strategies. Two whole-exome sequencing (WES) studies revealed that several pathways and driver genes, such as TP53, RB1, DLG2, PTEN, MYC, and MET, were mutated in both cOSA and its human counterpart [7, 8]. Driver mutations in MAPK/ERK and PI3K/AKT signaling pathways were identified in cOSA cell lines, and an anti-proliferative target inhibition using trametinib showed encouraging results, while alterations of the TP53 pathway were detected in non-sensitive cell lines [13]. These data highlight the importance of canine cancer cell lines as effective and reproducible pre-clinical models to provide crucial insights on pathogenetic mechanisms and drug response [14]. A deep mutational analysis of such in vitro models will allow the identification of new targets and offer valuable tools in translational medicine [18, 19], considering that integration of genomic data with drug screening is fundamental for the development and pre-clinical evaluation of novel treatments that would benefit canine and human patients
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