Zombie cancer cells give cold shoulder to chemotherapy

Cancer is the leading cause of disease-related death in childhood. This is in part due to cancer-associated genes called oncogenes that can be found far from chromosomes in cell nuclei on ring-shaped DNA inside tumor cells.

Circular extra-chromosomal DNA elements (ecDNA) are pieces of DNA that have broken off normal chromosomes and then been wrongly stitched together by DNA repair mechanisms. This phenomenon leads to circular DNA elements floating around in a cancer cell.

“We have shown that these ecDNAs are much more abundant in solid pediatric tumors than we previously thought,” said Lukas Chavez, PhD, an associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys. “And we have also shown that they are associated with very poor outcomes.”

An international team of scientists published findings August 7, 2025, in Cancer Discovery helping to explain why a common form of pediatric cancer called neuroblastoma is often treated successfully with chemotherapy but prone to relapse in several years.

Cancer cells with many copies of the MYCN oncogene on ecDNA grow quickly but are more easily destroyed by chemotherapy. Tumor cells with fewer copies of the oncogene located on ecDNA enter a zombie-like state known as senescence where they persist but no longer divide to make new cells. These zombie cells are unaffected by chemotherapy and can be reactivated a year or two later, triggering the cancer to relapse.

The researchers demonstrated that combining standard chemotherapy with a secondary therapy able to target senescent cancer cells led to dramatically improved outcomes in tests on mouse models of neuroblastoma. Ashley Hui, a graduate student in the Chavez lab, contributed to this study by showing that the phenomenon of zombie cells with low amounts of ecDNA carrying MYCN can also be observed in medulloblastoma, the most common malignant brain tumor type in children.

“By integrating genomic analyses of tumor DNA with hypothesis-driven functional experiments and high-throughput drug screening, we aim to discover new drugs and drug combinations that halt tumor growth by eliminating these oncogenic DNA circles,” said Chavez, a co-author of the study.

“Ultimately, our goal is to translate these scientific advances into more effective therapies and lasting cures for children with brain cancer.”

Giulia Montuori, PhD, a scientist at the Experimental and Clinical Research Center (ECRC) of the Max Delbrück Center (MDC) and Charité Berlin, is co-lead author of the study. Fengyu Tu, an associate researcher at Queen Mary University of London’s Barts Cancer Institute and Sun Yat-sen University, also is a co-lead author.

Jan R. Dörr, MD, PhD, a group leader at the ECRC of the MDC and Charité Berlin, is senior and co-corresponding author of the manuscript. Anton G. Henssen, MD, PhD, a group leader at the ECRC of the MDC and Charité Berlin, also is a co-corresponding author.

Additional authors include:

• Hui Hui from Sanford Burnham Prebys
• Rachel Schmargon, Elias Rodriguez-Fos, Konstantin Helmsauer, Lara Fankhänel, Bartolomeo Bosco, Bastiaan Spanjaard, Hannah Seyboldt, Laura Grunewald, Annette Künkele, Angelika Eggert, Susmita Mandal, Frank P.B. Dubois, Simon Schallenberg, Annika Lehmann, Teresa G. Krieger and Arend Koch from Charité Berlin
• Weini Huang from Sun Yat-sen University
• Benjamin Werner from Queen Mary University of London’s Barts Cancer Institute
• Di Qin, Matthias Jürgen Schmitt, Gaetano Gargiulo and Fabian Coscia from the Max Delbrück Center
• Karin Purshouse from The University of Edinburgh
• Dennis Gürgen from Experimental Pharmacology and Oncology
• Viktoria Buck and Mathias T. Rosenfeldt from Julius Maximilian University of Würzburg
• Jessica Theißen and Matthias Fischer from University Children’s Hospital of Cologne
• Sabine Taschner-Mandl from St. Anna Children’s Cancer Research Institute
• Patrick Hundsdoerfer from Helios Klinikum Berlin-Buch

The authors were supported by the China Scholarship Council, National Natural Science Foundation General Program, Deutsche Krebshilfe (German Cancer Aid), School of Oncology of the German Cancer Consortium, Kind-Philipp-Stiftung, Berlin Institute of Health, Charité Berlin, Barts Charity Lectureship and UK Research and Innovation. The study was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Cancer Institute, National Science Foundation, Deutsche Forschungsgemeinschaft, European Research Council, Federal Ministry of Education and Research, Cancer Research UK, Bruno and Helene Jöster Foundation, Clayes Foundation, St. Baldrick’s Foundation Hannah’s Heroes fund, Dragon Master Foundation and Children’s Brain Tumor Network.

The study’s DOI is 10.1158/2159-8290.CD-24-1738.