Structural variant and nucleosome occupancy dynamics postchemotherapy in a HER2+breast cancer organoid model

• 成果类型: Article
• 署名作者: Starostecka, Maja; Jeong, Hyobin; Hasenfeld, Patrick; Garagorri, Eva Benito -; Christiansen, Tania; Brasseur, Catherine Stober; Queiroz, Maise Gomes; Montero, Marta Garcia; Jechlinger, Martin; Korbel, Jan O.
• 署名单位: Bristol-Myers Squibb; European Molecular Biology Laboratory (EMBL); Yonsei University; Helmholtz Association; German Cancer Research Center (DKFZ); European Molecular Biology Laboratory (EMBL)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9918
• DOI: 10.1073/pnas.2415475122
• 发表日期: 2025-03-04
• 关键词: mutational processes; doxorubicin; signatures; EVOLUTION; SURVIVORS; network; cells

摘要

The most common chemotherapeutics induce DNA damage to eradicate cancer cells, yet defective DNA repair can propagate mutations, instigating therapy resistance and secondary malignancies. Structural variants (SVs), arising from copy- number- imbalanced and - balanced DNA rearrangements, are a major driver of tumor evolution, yet understudied posttherapy. Here, we adapted single- cell with nucleosome occupancy (NO) measurements obtained from the same single cell to enable simultaneous SV detection and cell- type classification. Using organoids fying a 7.4- fold increase in large chromosomal alterations post- doxorubicin. Complex DNA rearrangements, deletions, and duplications were prevalent across basal, luminal nucleosome occupancy levels on distinct cancer- related genes further underscore the multiomics established in this study paves the way for unraveling the most important of therapy on cancer evolution.