Bulk 3-prime RNA-sequencing of macrodissected neuroendocrine and exocrine tumor components of FFPE-embedded mouse gastric neuroendocrine carcinomas
Gastric neuroendocrine carcinomas (G-NEC) are aggressive malignancies with poorly understood biology and a lack of disease models. Here, we describe molecular and cellular hallmarks of G-NEC evolution and devise new avenues for its therapy. Using whole-genome sequencing, we characterize the genomic landscapes of human G-NEC and its histologic variants. We identify global and subtype-specific alterations and expose hitherto unappreciated gains of MYC family members in two-thirds of cases. Genetic engineering and lineage tracing in mice delineates an integrated cellular and molecular model of G-NEC evolution, which defines MYC as a critical driver and positions the cancer-cell-of-origin to the neuroendocrine compartment. MYC-driven tumors have pronounced metastatic competence and display defined signaling addictions, as revealed by large-scale genetic and pharmacologic screens. We created global maps of G-NEC dependencies, highlight critical vulnerabilities and validate across species new therapeutic targets, including candidates for immediate clinical drug repurposing.