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

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

Griger, Joscha; Widholz, Sebastian A; Jesinghaus, Moritz; de Andrade Krätzig, Niklas; Lange, Sebastian; Engleitner, Thomas; Montero, Juan José; Zhigalova, Ekaterina; Öllinger, Rupert; Suresh, Veveeyan; Winkler, Wiebke; Lier, Svenja; Baranov, Olga; Trozzo, Riccardo; Ben Khaled, Najib; Chakraborty, Shounak; Yu, Jiakun; Konukiewitz, Björn; Steiger, Katja; Pfarr, Nicole; Rajput, Ashish; Sailer, David; Keller, Gisela; Schirmacher, Peter; Röcken, Christoph; Fagerstedt, Klaus W; Mayerle, Julia; Schmidt...     »

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.      «

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 critic...     »