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


  • J. Griger
  • S.A. Widholz
  • M. Jesinghaus
  • N. de Andrade Krätzig
  • S. Lange
  • T. Engleitner
  • J.J. Montero
  • E. Zhigalova
  • R. Öllinger
  • V. Suresh
  • W. Winkler
  • S. Lier
  • O. Baranov
  • R. Trozzo
  • N. Ben Khaled
  • S. Chakraborty
  • J. Yu
  • B. Konukiewitz
  • K. Steiger
  • N. Pfarr
  • A. Rajput
  • D. Sailer
  • G. Keller
  • P. Schirmacher
  • C. Röcken
  • K.W. Fagerstedt
  • J. Mayerle
  • M. Schmidt-Supprian
  • G. Schneider
  • W. Weichert
  • D.P. Calado
  • T. Sommermann
  • G. Klöppel
  • K. Rajewsky
  • D. Saur
  • R. Rad


  • Cancer Cell


  • Cancer Cell 41 (7): 1327-1344.e10


  • 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.