Modeling canine hemangiosarcoma progression using patient-derived 2.5D organoids and orthotopic xenografts

Dogs commonly suffer from hemangiosarcoma (HSA) similar to human angiosarcoma (AS). The lack of adequate insight into the pathogenesis of canine HSA leads to clinical treatment failure. Thus, developing relevant preclinical models is instrumental for understanding disease and discovering new treatment strategies. In this study, we successfully generated canine HSA 2.5D organoids from patient-derived tumor tissues. After confirming specific marker expression in the organoids, we performed drug-sensitivity tests and compared the transcriptional patterns of HSA with those of nodular hyperplasia (NH) organoids to explore the mechanisms underlying malignant tumor development. Genes upregulated in the HSA group, such as Phospholipase A and Acyltransferase ( PLAAT)3, were identified as potential biomarkers for HSA. Gene knockdown experiments using siRNA as well as the chemical inhibition of PLAAT3 suppressed the invasion of HSA 2.5D organoid cells, with mild inhibition of proliferation. Furthermore, we established an orthotopic xenograft mouse model via splenic injection of HSA 2.5D organoid cells. The developed xenograft metastasized to other organs, and associated tissue pathology corresponded to the characteristics of the original tissues. In conclusion, the established 2.5D HSA organoid and xenograft model may present a new experimental platform for exploring novel therapeutic targets for both canine HSA and human AS.