TY  - JOUR
AU  - Issing, Christian
AU  - Menche, Constantin
AU  - Richter, Mara Romero
AU  - Mosa, Mohammed H
AU  - von der Grün, Jens
AU  - Fleischmann, Maximilian
AU  - Thoenissen, Philipp
AU  - Winkelmann, Ria
AU  - Darvishi, Tahmineh
AU  - Loth, Andreas G
AU  - Ghanaati, Shahram
AU  - Rödel, Franz
AU  - Wild, Peter J
AU  - Brandts, Christian H
AU  - Stöver, Timo
AU  - Farin, Henner F
TI  - Head and neck tumor organoid biobank for modelling individual responses to radiation therapy according to the TP53/HPV status.
JO  - Journal of experimental & clinical cancer research
VL  - 44
IS  - 1
SN  - 0392-9078
CY  - Heidelberg
PB  - Springer
M1  - DKFZ-2025-00503
SP  - 85
PY  - 2025
AB  - Head and neck cancers (HNC) represent an extremely heterogeneous group of diseases with a poorly predictable therapy outcome. Patient-derived tumor organoids (PDTO) offer enormous potential for individualized therapy testing and a better mechanistic understanding of the main HNC drivers.Here, we have established a comprehensive molecularly and functionally characterized head and neck organoid biobank (HNOB) recapitulating the clinically relevant subtypes of TP53 mutant and human papillomavirus type 16 (HPV 16) infection-driven HNC. Organoids were exposed to radiotherapy, and responses were correlated with clinical data. Genetically engineered normal and tumor organoids were used for testing the direct functional consequences of TP53-loss and HPV infection.The HNOB consisting of 18 organoid models, including 15 tumor models, was generated. We identified subtype-associated transcriptomic signatures and pathological features, including sensitivity to TP53 stabilization by the MDM2 inhibitor Nutlin-3. Furthermore, we describe an in vitro radio response assay revealing phenotypic heterogeneity linked to the individual patient's treatment outcome, including relapse probability. Using genetically engineered organoids, the possibility of co-existence of both cancer drivers was confirmed. TP53 loss, as well as HPV, increased growth in normal and tumor organoids. TP53 loss-of-function alone was insufficient to promote radiation resistance, whereas HPV 16 oncogenes E6/E7 mediated radiosensitivity via induction of cell cycle arrest.Our results highlight the translational value of the head and neck organoid models not only for patient stratification but also for mechanistic validation of therapy responsiveness of specific cancer drivers.
KW  - Humans
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Tumor Suppressor Protein p53: genetics
KW  - Head and Neck Neoplasms: radiotherapy
KW  - Head and Neck Neoplasms: virology
KW  - Head and Neck Neoplasms: pathology
KW  - Head and Neck Neoplasms: genetics
KW  - Organoids: virology
KW  - Biological Specimen Banks
KW  - Papillomavirus Infections: virology
KW  - Papillomavirus Infections: complications
KW  - Papillomavirus Infections: radiotherapy
KW  - Female
KW  - Male
KW  - CRISPR/Cas9 (Other)
KW  - Genetic editing (Other)
KW  - Head and neck squamous cell carcinoma (Other)
KW  - In vitro therapy testing (Other)
KW  - Preclinical model (Other)
KW  - Radioresistance (Other)
KW  - Tumor organoid biobank (Other)
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - TP53 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40045309
C2  - pmc:PMC11881459
DO  - DOI:10.1186/s13046-025-03345-3
UR  - https://inrepo02.dkfz.de/record/299559
ER  -