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

被引:16
作者
Griger, Joscha [1 ,2 ,3 ]
Widholz, Sebastian A. [1 ,2 ,3 ]
Jesinghaus, Moritz [4 ,6 ,7 ,13 ]
Kraetzig, Niklas de Andrade [1 ,2 ,3 ]
Lange, Sebastian [1 ,2 ,5 ]
Engleitner, Thomas [1 ,2 ]
Montero, Juan Jose [1 ,2 ]
Zhigalova, Ekaterina [1 ,2 ]
Oellinger, Rupert [1 ,2 ]
Suresh, Veveeyan [1 ,2 ]
Winkler, Wiebke [8 ]
Lier, Svenja [5 ]
Baranov, Olga [1 ,2 ]
Trozzo, Riccardo [1 ]
Ben Khaled, Najib [1 ,2 ,14 ]
Chakraborty, Shounak [4 ]
Yu, Jiakun [2 ]
Konukiewitz, Bjoern [4 ,9 ]
Steiger, Katja [4 ]
Pfarr, Nicole [4 ]
Rajput, Ashish [1 ,2 ]
Sailer, David [1 ,2 ,3 ]
Keller, Gisela [4 ]
Schirmacher, Peter [10 ]
Roecken, Christoph [9 ]
Fagerstedt, Klaus W. [15 ]
Mayerle, Julia
Schmidt-Supprian, Marc [1 ,3 ,16 ]
Schneider, Guenter [5 ,12 ]
Weichert, Wilko [4 ]
Calado, Dinis P. [8 ,11 ]
Sommermann, Thomas [8 ]
Kloeppel, Gueuronter [4 ]
Rajewsky, Klaus [8 ]
Saur, Dieter [2 ,3 ,5 ,13 ]
Rad, Roland [1 ,2 ,3 ,5 ]
机构
[1] Tech Univ Munich, Inst Mol Oncol & Funct Genom, Sch Med, D-81675 Munich, Germany
[2] Tech Univ Munich, Ctr Translat Canc Res TranslaTUM, Sch Med, D-81675 Munich, Germany
[3] German Canc Consortium DKTK, D-69120 Heidelberg, Germany
[4] Tech Univ Munich, Inst Pathol, Sch Med, D-81675 Munich, Germany
[5] Tech Univ Munich, Sch Med, Dept Med 2, Klinikum rechts Isar, D-81675 Munich, Germany
[6] Philipps Univ Marburg, Inst Pathol, Marburg, Germany
[7] Univ Hosp Marburg UKGM, Marburg, Germany
[8] Max Delbruck Ctr Mol Med Helmholtz Assoc, Immune Regulat & Canc, D-13125 Berlin, Germany
[9] Univ klinikum Schleswig Holstein Campus Kiel, Inst Pathol, D-24105 Kiel, Germany
[10] Univ klinikum Heidelberg, Inst Pathol, D-69120 Heidelberg, Germany
[11] Francis Crick Inst, Immun & Canc, London NW1 1AT, England
[12] Univ Med Ctr Gottingen, Dept Gen Visceral & Pediat Surg, D-37075 Gottingen, Germany
[13] Tech Univ Munich, Inst Expt Canc Therapy, Sch Med, D-81675 Munich, Germany
[14] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Med 2, D-81377 Munich, Germany
[15] Univ Helsinki, Dept Pathol, Helsinki, Finland
[16] Tech Univ Munich, Inst Expt Hematol, Sch Med, D-81675 Munich, Germany
基金
欧洲研究理事会;
关键词
C-MYC; STEM-CELLS; B-CELLS; DATABASE; STOMACH; SWITCH; IDENTIFICATION; TRANSCRIPTS; COMBINATION; INHIBITION;
D O I
10.1016/j.ccell.2023.06.001
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1327 / +
页数:29
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