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000299473 037__ $$aDKFZ-2025-00433
000299473 041__ $$aEnglish
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000299473 1001_ $$aStarostecka, Maja$$b0
000299473 245__ $$aStructural variant and nucleosome occupancy dynamics postchemotherapy in a HER2+ breast cancer organoid model.
000299473 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2025
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000299473 520__ $$aThe most common chemotherapeutics induce DNA damage to eradicate cancer cells, yet defective DNA repair can propagate mutations, instigating therapy resistance and secondary malignancies. Structural variants (SVs), arising from copy-number-imbalanced and -balanced DNA rearrangements, are a major driver of tumor evolution, yet understudied posttherapy. Here, we adapted single-cell template-strand sequencing (Strand-seq) to a HER2+ breast cancer model to investigate the formation of doxorubicin-induced de novo SVs. We coupled this approach with nucleosome occupancy (NO) measurements obtained from the same single cell to enable simultaneous SV detection and cell-type classification. Using organoids from TetO-CMYC/TetO-Neu/MMTV-rtTA mice modeling HER2+ breast cancer, we generated 459 Strand-seq libraries spanning various tumorigenesis stages, identifying a 7.4-fold increase in large chromosomal alterations post-doxorubicin. Complex DNA rearrangements, deletions, and duplications were prevalent across basal, luminal progenitor (LP), and mature luminal (ML) cells, indicating uniform susceptibility of these cell types to SV formation. Doxorubicin further elevated sister chromatid exchanges (SCEs), indicative of genomic stress persisting posttreatment. Altered nucleosome occupancy levels on distinct cancer-related genes further underscore the broad genomic impact of doxorubicin. The organoid-based system for single-cell multiomics established in this study paves the way for unraveling the most important therapy-associated SV mutational signatures, enabling systematic studies of the effect of therapy on cancer evolution.
000299473 536__ $$0G:(DE-HGF)POF4-312$$a312 - Funktionelle und strukturelle Genomforschung (POF4-312)$$cPOF4-312$$fPOF IV$$x0
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000299473 650_7 $$2Other$$abreast cancer
000299473 650_7 $$2Other$$aorganoids
000299473 650_7 $$2Other$$asingle-cell multi-omics
000299473 650_7 $$2Other$$astructural variation
000299473 650_7 $$2NLM Chemicals$$aNucleosomes
000299473 650_7 $$080168379AG$$2NLM Chemicals$$aDoxorubicin
000299473 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aReceptor, ErbB-2
000299473 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aERBB2 protein, human
000299473 650_2 $$2MeSH$$aNucleosomes: metabolism
000299473 650_2 $$2MeSH$$aOrganoids: metabolism
000299473 650_2 $$2MeSH$$aOrganoids: drug effects
000299473 650_2 $$2MeSH$$aFemale
000299473 650_2 $$2MeSH$$aBreast Neoplasms: drug therapy
000299473 650_2 $$2MeSH$$aBreast Neoplasms: genetics
000299473 650_2 $$2MeSH$$aBreast Neoplasms: metabolism
000299473 650_2 $$2MeSH$$aBreast Neoplasms: pathology
000299473 650_2 $$2MeSH$$aMice
000299473 650_2 $$2MeSH$$aHumans
000299473 650_2 $$2MeSH$$aDoxorubicin: pharmacology
000299473 650_2 $$2MeSH$$aAnimals
000299473 650_2 $$2MeSH$$aReceptor, ErbB-2: metabolism
000299473 650_2 $$2MeSH$$aReceptor, ErbB-2: genetics
000299473 650_2 $$2MeSH$$aSingle-Cell Analysis: methods
000299473 7001_ $$00000-0002-1526-3343$$aJeong, Hyobin$$b1
000299473 7001_ $$aHasenfeld, Patrick$$b2
000299473 7001_ $$aBenito-Garagorri, Eva$$b3
000299473 7001_ $$0P:(DE-He78)a1b80a5df1ba15f83efa7b523ecf2597$$aChristiansen, Tania$$b4
000299473 7001_ $$aStober Brasseur, Catherine$$b5
000299473 7001_ $$00000-0002-7189-0608$$aGomes Queiroz, Maise$$b6
000299473 7001_ $$aGarcia Montero, Marta$$b7
000299473 7001_ $$aJechlinger, Martin$$b8
000299473 7001_ $$0P:(DE-He78)372b77c2acf8604690a6a325a4e89287$$aKorbel, Jan$$b9$$eLast author$$udkfz
000299473 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.2415475122$$gVol. 122, no. 9, p. e2415475122$$n9$$pe2415475122$$tProceedings of the National Academy of Sciences of the United States of America$$v122$$x0027-8424$$y2025
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