Graduate Thesis Or Dissertation


The Role of Tumor-Derived Exosomes in the Development of Carboplatin Resistance in Canine Osteosarcoma Public Deposited

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  • Many humans and canines alike suffer from osteosarcoma, which is often metastatic, resistant to chemotherapy, and frequently fatal. The mechanisms through which osteosarcoma cells acquire resistance to chemotherapy are not entirely understood, and the role of exosomes as intercellular mediators of this resistance in osteosarcoma is unknown. Using established canine osteosarcoma cell lines, we developed carboplatin-resistant derivative lines, validated their resistance, characterized their respective phenotypes, and isolated their exosomes to understand how these phenotypes can be effectively transferred to chemotherapy sensitive cells. Our data suggests that the carboplatin-resistant sublines and their exosomes display variable phenotypes with potentiations of molecular strategies utilized in platinum resistance. The transcription factor β-catenin and the canonical Wnt signaling pathway may play a role in the promotion and maintenance of these respective phenotypes. Resistant cell-derived exosomes induce a drastic change in active β-catenin protein levels, transcriptional changes in β-catenin gene targets, and contain multiple effectors that may promote carboplatin resistance via multiple pathways. We isolated serum exosomes from two canine osteosarcoma patient cohorts that responded well and poorly to chemotherapy, respectively, and subjected these exosomes to proteomic analysis via LC-MS/MS. These data uncovered multiple potential prognostic markers in Tetranectin, Complement C2, Protein S, IGF-2, and Alpha-2-macroglobulin, with several functional roles and similarities to the carboplatin-resistant sublines.
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