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

Joscha Griger, Sebastian A. Widholz, Moritz Jesinghaus, Niklas de Andrade Krätzig, Sebastian Lange, Thomas Engleitner, Juan José Montero, Ekaterina Zhigalova, Rupert Öllinger, Veveeyan Suresh, Wiebke Winkler, Svenja Lier, Olga Baranov, Riccardo Trozzo, Najib Ben Khaled, Shounak Chakraborty, Jiakun Yu, Björn Konukiewitz, Katja Steiger, Nicole PfarrAshish Rajput, David Sailer, Gisela Keller, Peter Schirmacher, Christoph Röcken, Klaus W. Fagerstedt, Julia Mayerle, Marc Schmidt-Supprian, Günter Schneider, Wilko Weichert, Dinis P. Calado, Thomas Sommermann, Günter Klöppel, Klaus Rajewsky, Dieter Saur, Roland Rad

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)1327-1344.e10
JournalCancer Cell
Volume41
Issue number7
DOIs
StatePublished - 10 Jul 2023
Externally publishedYes

Keywords

  • CRISPR screen
  • MANEC
  • NEC
  • WGS
  • gastric cancer
  • genetic screening
  • mouse model
  • neuroendocrine cancer
  • pharmacologic screening
  • stomach

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