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

Item Type:Article
Title:An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets
Creators Name:Griger, J. and Widholz, S.A. and Jesinghaus, M. and de Andrade Krätzig, N. and Lange, S. and Engleitner, T. and Montero, J.J. and Zhigalova, E. and Öllinger, R. and Suresh, V. and Winkler, W. and Lier, S. and Baranov, O. and Trozzo, R. and Ben Khaled, N. and Chakraborty, S. and Yu, J. and Konukiewitz, B. and Steiger, K. and Pfarr, N. and Rajput, A. and Sailer, D. and Keller, G. and Schirmacher, P. and Röcken, C. and Fagerstedt, K.W. and Mayerle, J. and Schmidt-Supprian, M. and Schneider, G. and Weichert, W. and Calado, D.P. and Sommermann, T. and Klöppel, G. and Rajewsky, K. and Saur, D. and Rad, R.
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.
Keywords:Neuroendocrine Cancer, Stomach, Gastric Cancer, NEC, MANEC, WGS, Mouse Model, Genetic Screening, Pharmacologic Screening, CRISPR Screen, Animals, Mice
Source:Cancer Cell
Publisher:Cell Press / Elsevier
Page Range:1327-1344.e10
Date:10 July 2023
Official Publication:https://doi.org/10.1016/j.ccell.2023.06.001
PubMed:View item in PubMed

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