An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets.
Cancer Cell
; 41(7): 1327-1344.e10, 2023 07 10.
Article
em En
| MEDLINE
| ID: mdl-37352862
ABSTRACT
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
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Tumores Neuroendócrinos
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Carcinoma Neuroendócrino
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Cell
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2023
Tipo de documento:
Article