Coordinated inheritance of extrachromosomal DNA species in human cancer cells.

Autor:	Hung KL; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA., Jones MG; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA., Wong IT; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Lange JT; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Luebeck J; Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA., Scanu E; Department of Mathematics, Queen Mary University of London, London, UK., He BJ; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA., Brückner L; Max-Delbrück-Centrum für Molekulare Medizin (BIMSB/BIH), Berlin, Germany.; Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany., Li R; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA., González RC; Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.; Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany., Schmargon R; Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.; Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany., Dörr JR; Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.; Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany., Belk JA; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA., Bafna V; Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA., Werner B; Evolutionary Dynamics Group, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK., Huang W; Department of Mathematics, Queen Mary University of London, London, UK.; Group of Theoretical Biology, The State Key Laboratory of Biocontrol, School of Life Science, Sun Yat-sen University, Guangzhou, China., Henssen AG; Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.; Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.; German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center DKFZ, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Berlin Institute of Health, Anna-Louisa-Karsch-Str. 2, 10178, Berlin, Germany., Mischel PS; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Chang HY; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.; Department of Genetics, Stanford University, Stanford, CA, USA.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jul 19. Date of Electronic Publication: 2023 Jul 19.
DOI:	10.1101/2023.07.18.549597
Abstrakt:	The chromosomal theory of inheritance has dominated human genetics, including cancer genetics. Genes on the same chromosome segregate together while genes on different chromosomes assort independently, providing a fundamental tenet of Mendelian inheritance. Extrachromosomal DNA (ecDNA) is a frequent event in cancer that drives oncogene amplification, dysregulated gene expression and intratumoral heterogeneity, including through random segregation during cell division. Distinct ecDNA sequences, herein termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells. However, how multiple ecDNA species within a tumor cell are assorted and maintained across somatic cell generations to drive cancer cell evolution is not known. Here we show that cooperative ecDNA species can be coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. EcDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy number gains in multiple ecDNA species prior to any selection. Computational modeling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Finally, we show that coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations. Competing Interests: Competing Interests H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, Orbital Therapeutics, and an advisor of 10x Genomics, Arsenal Biosciences, Chroma Medicine, and Spring Discovery. V.B. is a co-founder, paid consultant, SAB member and has equity interest in Boundless Bio, inc. and Abterra, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. M.G.J. consults for and holds equity in Vevo Therapeutics. P.S.M. is a co-founder and advisor of Boundless Bio. The remaining authors declare no competing interests.
Databáze:	MEDLINE
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