Recombinase-induced genomic structural variants in neuroblastoma (RecoN)
Final Report Abstract
The project RecoN focussed on understanding the origins of complex structural genomic alterations involved in pediatric solid tumor formation with the goal to leverage these mechanistic insights to develop new therapies. During this project, we found that a variety of pediatric solid tumors, especially neuroblastomas and alveolar rhabdomyosarcomas, are highly sensitive to pharmacologic ATR inhibition. Mechanistically, replication stress induced by various oncogenic factors was found to contribute to this exquisite sensitivity. Based on our observations, clinical trials with ATR inhibitors were launched in Europe and the USA, which will hopefully identify pediatric patient populations that could benefit from such therapies. In the second part of this project that focused on elucidating the origins of structural variants, we made the surprising observation that most such alterations involve previously understudied extrachromosomal DNA (ecDNA). During collaborative research efforts with groups around the globe, others and we described new principles involved in ecDNA genesis, gene regulation and propagation in cancers. This identified new mechanisms involved in oncogene deregulation and cancer evaluation, with potentially important implications for the development of therapy resistance. Thus, the Emmy Noether programme enabled me to identify an emerging research field of interest (ecDNA) and its funding allowed us to make the first of hopefully many discoveries in this field.
Publications
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Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma. Nature Genetics, 52(1), 29-34.
Koche, Richard P.; Rodriguez-Fos, Elias; Helmsauer, Konstantin; Burkert, Martin; MacArthur, Ian C.; Maag, Jesper; Chamorro, Rocio; Munoz-Perez, Natalia; Puiggròs, Montserrat; Dorado, Garcia Heathcliff; Bei, Yi; Röefzaad, Claudia; Bardinet, Victor; Szymansky, Annabell; Winkler, Annika; Thole, Theresa; Timme, Natalie; Kasack, Katharina; Fuchs, Steffen ... & Henssen, Anton G.
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Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma. Nature Communications, 11(1).
Helmsauer, Konstantin; Valieva, Maria E.; Ali, Salaheddine; Chamorro, González Rocío; Schöpflin, Robert; Röefzaad, Claudia; Bei, Yi; Dorado, Garcia Heathcliff; Rodriguez-Fos, Elias; Puiggròs, Montserrat; Kasack, Katharina; Haase, Kerstin; Keskeny, Csilla; Chen, Celine Y.; Kuschel, Luis P.; Euskirchen, Philipp; Heinrich, Verena; Robson, Michael I.; Rosswog, Carolina ... & Koche, Richard P.
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Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma. Nature Cancer, 2(3), 312-326.
Roeschert, Isabelle; Poon, Evon; Henssen, Anton G.; Dorado, Garcia Heathcliff; Gatti, Marco; Giansanti, Celeste; Jamin, Yann; Ade, Carsten P.; Gallant, Peter; Schülein-Völk, Christina; Beli, Petra; Richards, Mark; Rosenfeldt, Mathias; Altmeyer, Matthias; Anderson, John; Eggert, Angelika; Dobbelstein, Matthias; Bayliss, Richard; Chesler, Louis ... & Eilers, Martin
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ecDNA hubs drive cooperative intermolecular oncogene expression. Nature, 600(7890), 731-736.
Hung, King L.; Yost, Kathryn E.; Xie, Liangqi; Shi, Quanming; Helmsauer, Konstantin; Luebeck, Jens; Schöpflin, Robert; Lange, Joshua T.; Chamorro, González Rocío; Weiser, Natasha E.; Chen, Celine; Valieva, Maria E.; Wong, Ivy Tsz-Lo; Wu, Sihan; Dehkordi, Siavash R.; Duffy, Connor V.; Kraft, Katerina; Tang, Jun; Belk, Julia A. ... & Chang, Howard Y.
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Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions. Nature Communications, 12(1).
Schmelz, Karin; Toedling, Joern; Huska, Matt; Cwikla, Maja C.; Kruetzfeldt, Louisa-Marie; Proba, Jutta; Ambros, Peter F.; Ambros, Inge M.; Boral, Sengül; Lodrini, Marco; Chen, Celine Y.; Burkert, Martin; Guergen, Dennis; Szymansky, Annabell; Astrahantseff, Kathy; Kuenkele, Annette; Haase, Kerstin; Fischer, Matthias; Deubzer, Hedwig E. ... & Eggert, Angelika
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Extrachromosomal DNA amplifications in cancer. Nature Reviews Genetics, 23(12), 760-771.
Yi, Eunhee; Chamorro, González Rocío; Henssen, Anton G. & Verhaak, Roel G. W.
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The evolutionary dynamics of extrachromosomal DNA in human cancers. Nature Genetics, 54(10), 1527-1533.
Lange, Joshua T.; Rose, John C.; Chen, Celine Y.; Pichugin, Yuriy; Xie, Liangqi; Tang, Jun; Hung, King L.; Yost, Kathryn E.; Shi, Quanming; Erb, Marcella L.; Rajkumar, Utkrisht; Wu, Sihan; Taschner-Mandl, Sabine; Bernkopf, Marie; Swanton, Charles; Liu, Zhe; Huang, Weini; Chang, Howard Y.; Bafna, Vineet ... & Mischel, Paul S.
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The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy. Nature Genetics, 54(2), 107-114.
van Leen, Eric; Brückner, Lotte & Henssen, Anton G.
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Therapeutic targeting of ATR in alveolar rhabdomyosarcoma. Nature Communications, 13(1).
Dorado, García Heathcliff; Pusch, Fabian; Bei, Yi; von Stebut, Jennifer; Ibáñez, Glorymar; Guillan, Kristina; Imami, Koshi; Gürgen, Dennis; Rolff, Jana; Helmsauer, Konstantin; Meyer-Liesener, Stephanie; Timme, Natalie; Bardinet, Victor; Chamorro, González Rocío; MacArthur, Ian C.; Chen, Celine Y.; Schulz, Joachim; Wengner, Antje M.; Furth, Christian ... & Henssen, Anton G.
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Elimusertib has Antitumor Activity in Preclinical Patient-Derived Pediatric Solid Tumor Models. Molecular Cancer Therapeutics, 23(4), 507-519.
Pusch, Fabian F.; Dorado, García Heathcliff; Xu, Robin; Gürgen, Dennis; Bei, Yi; Brückner, Lotte; Röefzaad, Claudia; von Stebut, Jennifer; Bardinet, Victor; Chamorro, Gonzalez Rocío; Eggert, Angelika; Schulte, Johannes H.; Hundsdörfer, Patrick; Seifert, Georg; Haase, Kerstin; Schäfer, Beat W.; Wachtel, Marco; Kühl, Anja A.; Ortiz, Michael V. ... & Henssen, Anton G.
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Mutational topography reflects clinical neuroblastoma heterogeneity. Cell Genomics, 3(10), 100402.
Rodriguez-Fos, Elias; Planas-Fèlix, Mercè; Burkert, Martin; Puiggròs, Montserrat; Toedling, Joern; Thiessen, Nina; Blanc, Eric; Szymansky, Annabell; Hertwig, Falk; Ishaque, Naveed; Beule, Dieter; Torrents, David; Eggert, Angelika; Koche, Richard P.; Schwarz, Roland F.; Haase, Kerstin; Schulte, Johannes H. & Henssen, Anton G.
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Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells. Nature Genetics, 55(5), 880-890.
Chamorro, González Rocío; Conrad, Thomas; Stöber, Maja C.; Xu, Robin; Giurgiu, Mădălina; Rodriguez-Fos, Elias; Kasack, Katharina; Brückner, Lotte; van Leen, Eric; Helmsauer, Konstantin; Dorado, Garcia Heathcliff; Stefanova, Maria E.; Hung, King L.; Bei, Yi; Schmelz, Karin; Lodrini, Marco; Mundlos, Stefan; Chang, Howard Y.; Deubzer, Hedwig E. ... & Henssen, Anton G.
