Journal Article

DKFZ-2025-00433

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural variant and nucleosome occupancy dynamics postchemotherapy in a HER2+ breast cancer organoid model.

Starostecka, M. ; Jeong, H. ; Hasenfeld, P. ; Benito-Garagorri, E. ; Christiansen, T.DKFZ* ; Stober Brasseur, C. ; Gomes Queiroz, M. ; Garcia Montero, M. ; Jechlinger, M. ; Korbel, J. (Last author)DKFZ*

2025
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.2415475122

Abstract: 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 template-strand sequencing (Strand-seq) to a HER2+ breast cancer model to investigate the formation of doxorubicin-induced de novo SVs. We coupled this approach with nucleosome occupancy (NO) measurements obtained from the same single cell to enable simultaneous SV detection and cell-type classification. Using organoids from TetO-CMYC/TetO-Neu/MMTV-rtTA mice modeling HER2+ breast cancer, we generated 459 Strand-seq libraries spanning various tumorigenesis stages, identifying a 7.4-fold increase in large chromosomal alterations post-doxorubicin. Complex DNA rearrangements, deletions, and duplications were prevalent across basal, luminal progenitor (LP), and mature luminal (ML) cells, indicating uniform susceptibility of these cell types to SV formation. Doxorubicin further elevated sister chromatid exchanges (SCEs), indicative of genomic stress persisting posttreatment. Altered nucleosome occupancy levels on distinct cancer-related genes further underscore the broad genomic impact of doxorubicin. The organoid-based system for single-cell multiomics established in this study paves the way for unraveling the most important therapy-associated SV mutational signatures, enabling systematic studies of the effect of therapy on cancer evolution.

Keyword(s): Nucleosomes: metabolism (MeSH) ; Organoids: metabolism (MeSH) ; Organoids: drug effects (MeSH) ; Female (MeSH) ; Breast Neoplasms: drug therapy (MeSH) ; Breast Neoplasms: genetics (MeSH) ; Breast Neoplasms: metabolism (MeSH) ; Breast Neoplasms: pathology (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Doxorubicin: pharmacology (MeSH) ; Animals (MeSH) ; Receptor, ErbB-2: metabolism (MeSH) ; Receptor, ErbB-2: genetics (MeSH) ; Single-Cell Analysis: methods (MeSH) ; breast cancer ; organoids ; single-cell multi-omics ; structural variation ; Nucleosomes ; Doxorubicin ; Receptor, ErbB-2 ; ERBB2 protein, human

Note: #LA:B480#

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Contributing Institute(s):

1. Mechanismen der genetischen Variation und Datenwissenschaft (B480)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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