New research shows how circular extrachromosomal DNA (ecDNA), found in nearly 1 in 5 cancers, co-segregate during mitosis to drive tumor evolution. A trio of Nature research articles examine how ecDNA forms, is inherited, and propagates oncogenic traits, demonstrating that the circular molecules serve as a platform for massive oncogene expression and the formation of novel regulatory circuits that endow survival advantages, such as immune system suppression. This deep dive into the mechanisms by which ecDNA put cancer into overdrive resulted in the first therapeutic targeting of these circular molecules to treat cancer in preclinical models.
How ecDNA supercharges cancer
The acentric structure of ecDNA promotes intratumoral genetic heterogeneity, highly elevated copy number, random segregation, and quick tumor evolution. When they cluster in the nucleus, ecDNA can generate new, functional enhancer-promoter interactions and evolve novel gene regulatory relationships. This accelerated evolution and ability to explore genetic and epigenetic space is challenged by its potentially transient nature—a winning combination of ecDNA may not be present in the next daughter cell generation if they are randomly transmitted. Yet, these circular molecules have been difficult to drug, and no ecDNA therapeutics exist on the market.
Two of the three Nature research articles go on a deep dive into the origins, inheritance, and impact of ecDNA. In one of the articles, Chris Bailey and Oriol Pich, co-lead authors, analyzed the largest single collection of whole genome sequenced cancer patient samples available today. By analyzing data from 14,778 patients with 39 tumor types from the 100,000 Genomes Project, Bailey and Pich demonstrated that 17.1% of tumor samples contain ecDNA. This analysis revealed the incredible diversity of ecDNA elements across cancer and shed light on the related tissue and genetic contexts, as well as the mutational processes that ecDNA is associated with. Bailey and Pich also discovered that ecDNA is associated with poor survival even after controlling for underlying genome instability, implying that ecDNA-specific effects contribute to poor patient outcomes and, as a result, yet-to-be-discovered therapeutic vulnerabilities.
In a parallel effort, a group of co-lead authors—King L. Hung, Matthew G. Jones, Ivy Tsz-Lo Wong, and Ellis J. Curtis—used single-cell sequencing, imaging, evolutionary modeling, and chemical perturbations across multiple cancer types to show that ecDNA species co-occur in cancer cells and co-segregate during mitosis. Coordinated inheritance of ecDNAs bestow stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations. Hung, Jones, Wong, and Curtis demonstrate that the result is a “jackpot effect” that promotes cooperation among heterogeneous ecDNAs, allowing for the co-amplification of multiple oncogenes and the continued diversification of cancer genomes.
An oncogenic Achilles’ heel
In the third paper, co-lead authors Jun Tang, Natasha E. Weiser, and Guiping Wang showed that ecDNA provides a transcriptional advantage that drives tumor evolution via massive oncogene expression and rapid genome adaptation, which can be used to target ecDNA-containing tumors selectively. The paper demonstrates how ecDNA transcription begins to run wild and comes into conflict with replication processes, causing single- and double-stranded DNA breaks. However, they discovered that cancer cells have several mechanisms that lessen the direct and indirect effects of the transcription-replication conflict, such as a strong dependence on CHK1, an S-phase checkpoint kinase activator. Tang, Weiser, and Wang continue by demonstrating how BBI-2779, a highly selective, potent, and bioavailable oral CHK1 inhibitor, preferentially destroys tumor cells that contain ecDNA and causes significant and long-lasting tumor regression in mice in a gastric cancer model.
All three papers are the work of Team eDyNAmiC and its international collaborators to study ecDNA from various perspectives. Through Cancer Grand Challenges, Team eDyNAmiC is funded by Cancer Research UK and the U.S. National Cancer Institute, with support to Cancer Research UK from Emerson Collective and the Kamini and Vindi Banga Family Trust. Stanford physician-scientist and Howard Hughes Medical Institute (HHMI) investigator Howard Y. Chang, MD, PhD, co-led two of the studies along with Paul Mischel, MD, a fellow Stanford University colleague who served as a lead on all three papers.
