THU487 Xenograft of VHL-deficient Pancreatic Neuroendocrine Neoplasm Cells - A Novel Low-grade PNEN In Vivo Model

Abstract Disclosure: A. Telerman: None. Y. Yossef: None. A. Chmelnik: None. A. Tirosh: None. Background: Von Hippel-Lindau (VHL) disease is a familial cancer syndrome caused by a germline mutation in the VHL tumor suppressor gene. Although VHL-related pancreatic neuroendocrine neoplasms (vPNEN) have been studied, their molecular pathogenesis is not fully understood. Aims: To generate a mouse model for studying the mechanisms that promote vPNEN development in vivo. Methods: We induced a frameshift mutation in VHL using the CRISPR/Cas9 technique in the BON1 cell line, originating from high-grade PNEN (FS-BON1). We validated the pseudohypoxic nature of the cells by real-time polymerase chain reaction of VEGF and EPO in FS-BON1 compared to VHL wild-type BON1 (WT-BON1). We compared cell line-derived xenografts (CDXs) growth in athymic Nude-Foxn1nu female mice injected with WT-BON1 (n=9), FS-BON1 (n=9) and media (purified bovine serum, n=5). Tumor diameter and calculated volume and mice weight were recorded weekly. Plasma chromogranin A (CgA) levels were measured in mice sera by ELISA. Results: FS-BON1 showed upregulation of VEGF and EPO compared with WT-BON1, confirming their pseudohypoxic microenvironment. At 14 weeks, 0/9 FS-BON1 CDX reached a volume of 1 cm3 compared with 5/9 of the WT-BON1 group (p=0.03). In time-dependent analysis, FS-BON1-derived xenografts grew significantly slower than WT-BON1 xenografts (p=0.02). No significant differences in CgA serum levels were found between the mice groups. Conclusions: We report a new pseudohypoxic in vivo PNEN model. The pVHL-deficient cells show an unexpected indolent course, suggesting it as a new model for low-grade PNEN. This CDX mouse model can be utilized in further studies to evaluate the mechanism responsible for vPNEN development and for evaluating interventions in low-grade PNEN. Presentation: Thursday, June 15, 2023