Abstract 3912: Transcriptional heterogeneity between hemangiosarcoma and nodular hyperplasia using patient-derived cell lines and orthotopic xenograft model revealed new therapeutic targets

Abstract Human angiosarcoma (AS) is a rare and aggressive subtype of soft tissue sarcoma of endothelial cell origin with a propensity for local recurrence and metastasis. The optimal treatment of metastatic AS is unclear and is associated with a generally poor prognosis unless diagnosed early. The lack of insight into the pathogenesis always causes treatment failure in the clinic. To discover new treatment strategies for AS, it is necessary to develop new and relevant preclinical models for AS. Dogs commonly suffer from a similar neoplasm, called hemangiosarcoma (HA), with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. Angiosarcomas and HA were reported to share pathology, immunohistochemical characteristics, and molecular signatures. Therefore, HA is considered a closer preclinical model for advancing AS research than rodent models. In veterinary clinic, malignant HA always occurs with nodular hyperplasia (NH), a kind of benign tumor. However, the AS orthotopic xenograft mouse still needs standard guidelines for validation. In this study, we successfully generated 5 canine HA cell lines from fresh patient tumor tissues. We compared the RNA sequencing data between HA and NH patient-derived cell strains (5:5). Data revealed that pathways related to autophagy and lysosomal membrane were found upregulated in HA compared to NH. Additionally, PIK3IP1, HIP1, PLAAT3, and MARVELD3 can be considered potential pharmacological targets and biomarkers for HA. Furthermore, we established an orthotopic xenograft model on mouse spleen using canine patient-derived HA cell lines by splenic injection. The results of xenograft spleen mass and drug screening test of toceranib, carboplatin, doxorubicin and cyclophosphamide using xenograft mouse HA cells showed corresponded sensitivity, supported that our model could maintain the original features of the patient tumor. In conclusion, the transcriptional difference between HA and NH might provide a better understanding of the progress of blood vessel sarcoma, and new pharmacological targets and biomarkers for diagnosis. Also, the xenograft model study may provide a reference for both AS and HA therapeutic predictions in basic medical science. Citation Format: Yishan Liu, Haru Yamamoto, Mohamed Elbadawy, Amira Abugomaa, Tatsuya Usui, Kazuaki Sasaki. Transcriptional heterogeneity between hemangiosarcoma and nodular hyperplasia using patient-derived cell lines and orthotopic xenograft model revealed new therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3912.