Abstract SY20-01: Intercellular DNA transfer drives the emergence of ecDNA-like elements

The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mis-localization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromosomes. Beyond activating cell-autonomous signaling programs, whether such cytoplasmic DNA can elicit non-cell autonomous consequences to nearby cells remains unclear. Here we show that cytoplasmic DNAs undergo intercellular transfer through contact-dependent, cytoskeleton-based nanotube structures connecting adjacent human cells. Diverse sources of genomic instability - including exposure to mitotic spindle poisons, ionizing radiation, and Cas9-induced chromosome breakage - promote nanotube-mediated DNA transfer in both cancer and non-cancerous cells. Transferred DNA fragments are stably inherited as functional extrachromosomal DNA (ecDNA) elements in the recipient host genome, thereby conferring heritable phenotypic traits to the recipient cell. Our findings uncover a horizontal gene transfer-like mechanism through which direct cell-cell contact can propagate genomic instability and reshape mammalian genomes. Citation Format: Peter Ly. Intercellular DNA transfer drives the emergence of ecDNA-like elements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY20-01.