Inverted logic of ecDNA localization converts nuclear periphery into oncogenic transcription hubs in cancer
Year: 2026
Type: preprint
Abstract: Extrachromosomal DNA (ecDNA) is a major driver of cancer pathogenesis, however, its spatial organization in the nucleus is not currently understood. Here we show that ecDNAs, in contrast to chromosomal DNA, preferentially localize to the nuclear periphery yet resist peripheral gene silencing. Single-molecule multi-omic sequencing and imaging-based CRISPR screening demonstrate enhanced ecDNA hub formation, H3K27ac and H3K9me3 bivalency, late DNA replication, long-range CpG hypomethylation, and increased transcriptional output when ecDNAs localize to the nuclear periphery. EcDNA anchors to the nuclear lamina through H3K9me3-dependent interactions with the Lamin B Receptor (LBR), which if interrupted, results in inward migration of ecDNA particles, reduced ecDNA congregation, and decreased transcription of ecDNA-encoded genes. These results reveal inherent advantages of the spatial organization of ecDNA that are not available to chromosomal DNA, enhancing ecDNA congregation and amplifying oncogenic transcriptional output, by localizing to the nuclear periphery of cancer cells.
Authors: Yanbo Wang, Xiaowei Yan, Natasha E. Weiser, Ivy Tsz-Lo Wong, Shu Zhang, Yung-Hsin Huang, Rui Li, Katerina Kraft, Aditi Gnanasekar, Jun Tang, Cy Chittenden, Lotte Brückner, Imran Noorani, Charles Swanton, Anton G. Henssen, Andrew B. Stergachis, Nicolas Altemose, Howard Y. Chang, Paul S. Mischel
Institutions: Stanford Medicine, Stanford University, Yale University, Amgen (United States), Max Delbrück Center, Charité – Universitätsmedizin Berlin, The Francis Crick Institute, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, University College Hospital, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung, University of Washington, Brotman Baty Institute, Chan Zuckerberg Biohub San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213508875