An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets

Cancer Cell. 2023 Jul 10;41(7):1327-1344.e10. doi: 10.1016/j.ccell.2023.06.001. Epub 2023 Jun 22.


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.

Keywords: CRISPR screen; MANEC; NEC; WGS; gastric cancer; genetic screening; mouse model; neuroendocrine cancer; pharmacologic screening; stomach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Neuroendocrine* / drug therapy
  • Carcinoma, Neuroendocrine* / genetics
  • Carcinoma, Neuroendocrine* / metabolism
  • Humans
  • Mice
  • Models, Molecular
  • Neuroendocrine Tumors* / drug therapy
  • Neuroendocrine Tumors* / genetics
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism