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

被引：20

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

来源：

CANCER CELL | 2023年 / 41卷 / 07期

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

页码：1327 / +

页数：29

共 125 条

[1]

[Anonymous], Picard tools-by broad institute

[2] Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3) [J].

Apostolidis, Leonidas ;

Dal Buono, Arianna ;

Merola, Elettra ;

Jann, Henning ;

Jaeger, Dirk ;

Wiedenmann, Bertram ;

Winkler, Eva Caroline ;

Pavel, Marianne .

CANCERS, 2021, 13 (08)

[3] Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study [J].

Arnold, Melina ;

Rutherford, Mark J. ;

Bardot, Aude ;

Ferlay, Jacques ;

Andersson, Therese M-L ;

Myklebust, Tor Age ;

Tervonen, Hanna ;

Thursfield, Vicky ;

Ransom, David ;

Shack, Lorraine ;

Woods, Ryan R. ;

Turner, Donna ;

Leonfellner, Suzanne ;

Ryan, Susan ;

Saint-Jacques, Nathalie ;

De, Prithwish ;

McClure, Carol ;

Ramanakumar, Agnihotram V. ;

Stuart-Panko, Heather ;

Engholm, Gerda ;

Walsh, Paul M. ;

Jackson, Christopher ;

Vernon, Sally ;

Morgan, Eileen ;

Gavin, Anna ;

Morrison, David S. ;

Huws, Dyfed W. ;

Porter, Geoff ;

Butler, John ;

Bryant, Heather ;

Currow, David C. ;

Hiom, Sara ;

Parkin, D. Max ;

Sasieni, Peter ;

Lambert, Paul C. ;

Moller, Bjorn ;

Soerjomataram, Isabelle ;

Bray, Freddie .

LANCET ONCOLOGY, 2019, 20 (11) :1493-1505

[4] Gene Ontology: tool for the unification of biology [J].

Ashburner, M ;

Ball, CA ;

Blake, JA ;

Botstein, D ;

Butler, H ;

Cherry, JM ;

Davis, AP ;

Dolinski, K ;

Dwight, SS ;

Eppig, JT ;

Harris, MA ;

Hill, DP ;

Issel-Tarver, L ;

Kasarskis, A ;

Lewis, S ;

Matese, JC ;

Richardson, JE ;

Ringwald, M ;

Rubin, GM ;

Sherlock, G .

NATURE GENETICS, 2000, 25 (01) :25-29

[5] Ordered and deterministic cancer genome evolution after p53 loss [J].

Baslan, Timour ;

Morris, John P. ;

Zhao, Zhen ;

Reyes, Jose ;

Ho, Yu-Jui ;

Tsanov, Kaloyan M. ;

Bermeo, Jonathan ;

Tian, Sha ;

Zhang, Sean ;

Askan, Gokce ;

Yavas, Aslihan ;

Lecomte, Nicolas ;

Erakky, Amanda ;

Varghese, Anna M. ;

Zhang, Amy ;

Kendall, Jude ;

Ghiban, Elena ;

Chorbadjiev, Lubomir ;

Wu, Jie ;

Dimitrova, Nevenka ;

Chadalavada, Kalyani ;

Nanjangud, Gouri J. ;

Bandlamudi, Chaitanya ;

Gong, Yixiao ;

Donoghue, Mark T. A. ;

Socci, Nicholas D. ;

Krasnitz, Alex ;

Notta, Faiyaz ;

Leach, Steve D. ;

Iacobuzio-Donahue, Christine A. ;

Lowe, Scott W. .

NATURE, 2022, 608 (7924) :795-+

[6] Comprehensive molecular characterization of gastric adenocarcinoma [J].

Bass, Adam J. ;

Thorsson, Vesteinn ;

Shmulevich, Ilya ;

Reynolds, Sheila M. ;

Miller, Michael ;

Bernard, Brady ;

Hinoue, Toshinori ;

Laird, Peter W. ;

Curtis, Christina ;

Shen, Hui ;

Weisenberger, Daniel J. ;

Schultz, Nikolaus ;

Shen, Ronglai ;

Weinhold, Nils ;

Keiser, David P. ;

Bowlby, Reanne ;

Sipahimalani, Payal ;

Cherniack, Andrew D. ;

Getz, Gad ;

Liu, Yingchun ;

Noble, Michael S. ;

Pedamallu, Chandra ;

Sougnez, Carrie ;

Taylor-Weiner, Amaro ;

Akbani, Rehan ;

Lee, Ju-Seog ;

Liu, Wenbin ;

Mills, Gordon B. ;

Yang, Da ;

Zhang, Wei ;

Pantazi, Angeliki ;

Parfenov, Michael ;

Gulley, Margaret ;

Piazuelo, M. Blanca ;

Schneider, Barbara G. ;

Kim, Jihun ;

Boussioutas, Alex ;

Sheth, Margi ;

Demchok, John A. ;

Rabkin, Charles S. ;

Willis, Joseph E. ;

Ng, Sam ;

Garman, Katherine ;

Beer, David G. ;

Pennathur, Arjun ;

Raphael, Benjamin J. ;

Wu, Hsin-Ta ;

Odze, Robert ;

Kim, Hark K. ;

Bowen, Jay .

NATURE, 2014, 513 (7517) :202-209

[7] Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy [J].

Beaulieu, Marie-Eve ;

Jauset, Toni ;

Masso-Valles, Daniel ;

Martinez-Martin, Sandra ;

Rahl, Peter ;

Maltais, Loika ;

Zacarias-Fluck, Mariano F. ;

Casacuberta-Serra, Silvia ;

Serrano del Pozo, Erika ;

Fiore, Christopher ;

Foradada, Laia ;

Castillo Cano, Virginia ;

Sanchez-Hervas, Meritxell ;

Guenther, Matthew ;

Romero Sanz, Eduardo ;

Oteo, Marta ;

Tremblay, Cynthia ;

Martin, Genesis ;

Letourneau, Danny ;

Montagne, Martin ;

Morcillo Alonso, Miguel Angel ;

Whitfield, Jonathan R. ;

Lavigne, Pierre ;

Soucek, Laura .

SCIENCE TRANSLATIONAL MEDICINE, 2019, 11 (484)

[8] Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer [J].

Beltran, Himisha ;

Prandi, Davide ;

Mosquera, Juan Miguel ;

Benelli, Matteo ;

Puca, Loredana ;

Cyrta, Joanna ;

Marotz, Clarisse ;

Giannopoulou, Eugenia ;

Chakravarthi, Balabhadrapatruni V. S. K. ;

Varambally, Sooryanarayana ;

Tomlins, Scott A. ;

Nanus, David M. ;

Tagawa, Scott T. ;

Van Allen, Eliezer M. ;

Elemento, Olivier ;

Sboner, Andrea ;

Garraway, Levi A. ;

Rubin, Mark A. ;

Demichelis, Francesca .

NATURE MEDICINE, 2016, 22 (03) :298-305

[9] A continuum model for tumour suppression [J].

Berger, Alice H. ;

Knudson, Alfred G. ;

Pandolfi, Pier Paolo .

NATURE, 2011, 476 (7359) :163-169

[10] Trimmomatic: a flexible trimmer for Illumina sequence data [J].

Bolger, Anthony M. ;

Lohse, Marc ;

Usadel, Bjoern .

BIOINFORMATICS, 2014, 30 (15) :2114-2120

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