An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets
Menée à l'aide de lignées cellulaires, d'organoïdes, de modèles murins et d'échantillons tumoraux issus de patients atteints d'un carcinome gastrique neuroendocrinien, cette étude examine les caractéristiques génomiques de ce type de tumeur
Gastric neuroendocrine carcinomas (G-NEC) are aggressive malignancies with poorly understood biology and a lack of disease models. Here, we use genome sequencing to 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 a large part of cases. Genetic engineering and lineage tracing in mice delineate a 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 screening of cell lines and organoid resources. We create global maps of G-NEC dependencies, highlight critical vulnerabilities, and validate therapeutic targets, including candidates for clinical drug repurposing. Our study gives comprehensive insights into G-NEC biology.
Cancer Cell , résumé, 2022