2. Academic Validation
  3. Engineered extrachromosomal oncogene amplifications promote tumorigenesis

Engineered extrachromosomal oncogene amplifications promote tumorigenesis

  • Nature. 2024 Dec 18. doi: 10.1038/s41586-024-08318-8.
Davide Pradella # 1,  Minsi Zhang # 1 2,  Rui Gao # 1 3,  Melissa A Yao # 1 3,  Katarzyna M Gluchowska 1,  Ylenia Cendon-Florez 1,  Tanmay Mishra 1 4,  Gaspare La Rocca 1,  Moritz Weigl 1,  Ziqi Jiao 1 3,  Hieu H M Nguyen 1,  Marta Lisi 5,  Mateusz M Ozimek 1,  Chiara Mastroleo 1,  Kevin Chen 1,  Felix Grimm 1,  Jens Luebeck 6,  Shu Zhang 7 8 9 10,  Andrea Alice Zolli 1,  Eric G Sun 1 11,  Bhargavi Dameracharla 6,  Zhengqiao Zhao 12,  Yuri Pritykin 12,  Carlie Sigel 13,  Howard Y Chang 7 8 14,  Paul S Mischel 9 10,  Vineet Bafna 6 15,  Cristina R Antonescu 13,  Andrea Ventura 16
Affiliations

Affiliations

  • 1 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Louis V. Gerstner Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 BCMB Allied program, Weill Cornell Medicine Graduate School for Medical Sciences, New York, NY, USA.
  • 5 Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Computer Science and Engineering, UC San Diego, La Jolla, CA, USA.
  • 7 Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
  • 8 Department of Dermatology and Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 9 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 10 Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • 11 Tri-Institutional MD-PhD Program, Weill Cornell Medicine, Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 12 Lewis-Sigler Institute for Integrative Genomics and Department of Computer Science, Princeton University, Princeton, NJ, USA.
  • 13 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 14 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 15 Halicioglu Data Science Institute, UC San Diego, La Jolla, CA, USA.
  • 16 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. venturaa@mskcc.org.
  • # Contributed equally.
PMID: 39695225 DOI: 10.1038/s41586-024-08318-8
Abstract

Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs)2 in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these Animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumour formation in an autochthonous mouse model of hepatocellular carcinoma. These findings offer insights into the role of ecDNA-mediated gene amplifications in tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications.

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