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| Item Type: | Article |
|---|---|
| Title: | An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets |
| Creators: |
Griger, J., Widholz, S.A., Jesinghaus, M., de Andrade Krätzig, N., Lange, S., Engleitner, T., Montero, J.J., Zhigalova, E., Öllinger, R., Suresh, V., Winkler, W.  ORCID: https://orcid.org/0000-0001-8807-9259, Lier, S., Baranov, O., Trozzo, R., Ben Khaled, N., Chakraborty, S., Yu, J., Konukiewitz, B., Steiger, K., Pfarr, N., Rajput, A., Sailer, D., Keller, G., Schirmacher, P., Röcken, C., Fagerstedt, K.W., Mayerle, J., Schmidt-Supprian, M., Schneider, G., Weichert, W., Calado, D.P. ORCID: https://orcid.org/0000-0001-8239-7184, Sommermann, T. ORCID: https://orcid.org/0000-0003-2899-0256, Klöppel, G., Rajewsky, K. ORCID: https://orcid.org/0000-0002-6633-6370, 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 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 41 |
| Number: | 7 |
| 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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