% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Starostecka:299473,
      author       = {M. Starostecka and H. Jeong and P. Hasenfeld and E.
                      Benito-Garagorri and T. Christiansen$^*$ and C. Stober
                      Brasseur and M. Gomes Queiroz and M. Garcia Montero and M.
                      Jechlinger and J. Korbel$^*$},
      title        = {{S}tructural variant and nucleosome occupancy dynamics
                      postchemotherapy in a {HER}2+ breast cancer organoid model.},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {122},
      number       = {9},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {DKFZ-2025-00433},
      pages        = {e2415475122},
      year         = {2025},
      note         = {#LA:B480#},
      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.},
      keywords     = {Nucleosomes: metabolism / Organoids: metabolism /
                      Organoids: drug effects / Female / Breast Neoplasms: drug
                      therapy / Breast Neoplasms: genetics / Breast Neoplasms:
                      metabolism / Breast Neoplasms: pathology / Mice / Humans /
                      Doxorubicin: pharmacology / Animals / Receptor, ErbB-2:
                      metabolism / Receptor, ErbB-2: genetics / Single-Cell
                      Analysis: methods / breast cancer (Other) / organoids
                      (Other) / single-cell multi-omics (Other) / structural
                      variation (Other) / Nucleosomes (NLM Chemicals) /
                      Doxorubicin (NLM Chemicals) / Receptor, ErbB-2 (NLM
                      Chemicals) / ERBB2 protein, human (NLM Chemicals)},
      cin          = {B480},
      ddc          = {500},
      cid          = {I:(DE-He78)B480-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39993200},
      doi          = {10.1073/pnas.2415475122},
      url          = {https://inrepo02.dkfz.de/record/299473},
}