This project generates human pluripotent stem cell (hPSC)-derived designer organoids to model cell-of-origin effects and early oncogenic transformation in pancreatic neuroendocrine tumors (PanNET). Starting from defined genetic backgrounds, doctoral researchers will differentiate hPSCs into pancreatic endocrine lineages, introduce PanNET-relevant mutations, and establish long-term ex vivo organoid cultures that recapitulate tumor initiation from precursor lesions. Comprehensive multiomics profiling (scRNA-seq, spatial transcriptomics), functional assays, and biomarker validation across core facilities will dissect mutational signatures driving tumor subtype heterogeneity (e.g., well-differentiated vs. poorly differentiated), cell-of-origin dependencies, and early transformation events. The work identifies conserved oncogenic trajectories, stratification biomarkers for clinical risk assessment, and precision therapy vulnerabilities, contributing shared outcomes across Org-BOOST pillars for improved PanNET diagnosis and targeted intervention.