Journal article
Subclonal response heterogeneity to define cancer organoid therapeutic sensitivity
Scientific reports, Vol.15(1), 12072
04/09/2025
DOI: 10.1038/s41598-025-96204-2
PMCID: PMC11978853
PMID: 40200028
Abstract
Tumor heterogeneity is predicted to confer inferior clinical outcomes with precision-based strategies, however, modeling heterogeneity in a manner that still represents the tumor of origin remains a formidable challenge. Sequencing technologies are limited in their ability to identify rare subclonal populations and predict response to treatments for patients. Patient-derived organotypic cultures have significantly improved the modeling of cancer biology by faithfully representing the molecular features of primary malignant tissues. Patient-derived cancer organoid (PCO) cultures contain subclonal populations with the potential to recapitulate heterogeneity, although treatment response assessments commonly ignore diversity in the molecular profile or treatment response. Here, we demonstrate the advantage of evaluating individual PCO heterogeneity to enhance the sensitivity of these assays for predicting clinical response. Additionally, organoid subcultures identify subclonal populations with altered treatment response. Finally, dose escalation studies of PCOs to targeted anti-EGFR therapy are utilized which reveal divergent pathway expression when compared to pretreatment cultures. Overall, these studies demonstrate the importance of population-based organoid response assessments, the use of PCOs to identify molecular heterogeneity not observed with bulk tumor sequencing, and PCO heterogeneity for understanding therapeutic resistance mechanisms.
Details
- Title: Subtitle
- Subclonal response heterogeneity to define cancer organoid therapeutic sensitivity
- Creators
- Jeremy D Kratz - William S. Middleton Memorial Veterans HospitalShujah Rehman - University of Wisconsin–MadisonKatherine A Johnson - University of Wisconsin–MadisonAmani A Gillette - University of Wisconsin–MadisonAishwarya Sunil - University of Wisconsin–MadisonPeter F Favreau - University of Wisconsin–MadisonCheri A Pasch - University of Wisconsin Carbone Cancer CenterDevon Miller - University of Wisconsin Carbone Cancer CenterLucas C Zarling - University of Wisconsin Carbone Cancer CenterAustin H Yeung - University of Wisconsin Carbone Cancer CenterLinda Clipson - University of Wisconsin–MadisonSamantha J Anderson - University of Wisconsin Carbone Cancer CenterAlyssa K Steimle - University of Wisconsin Carbone Cancer CenterCarley M Sprackling - University of Wisconsin Carbone Cancer CenterKayla K Lemmon - University of Wisconsin Carbone Cancer CenterDaniel E Abbott - University of Wisconsin–MadisonMark E Burkard - University of Wisconsin Carbone Cancer CenterMichael F Bassetti - University of Wisconsin–MadisonJens C Eickhoff - University of Wisconsin Carbone Cancer CenterEugene F Foley - University of Wisconsin–MadisonCharles P Heise - University of Wisconsin–MadisonRandall J Kimple - University of Wisconsin–MadisonElise H Lawson - University of Wisconsin–MadisonNoelle K LoConte - University of Wisconsin Carbone Cancer CenterSam J Lubner - William S. Middleton Memorial Veterans HospitalDaniel L Mulkerin - University of Wisconsin Carbone Cancer CenterKristina A Matkowskyj - University of Wisconsin School of Medicine and Public HealthCristina B Sanger - University of Wisconsin–MadisonNataliya V Uboha - University of Wisconsin Carbone Cancer CenterSean J Mcilwain - University of Wisconsin–MadisonIrene M Ong - University of Wisconsin–MadisonEvie H Carchman - University of Wisconsin–MadisonMelissa C Skala - University of Wisconsin–MadisonDustin A Deming - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.15(1), 12072
- DOI
- 10.1038/s41598-025-96204-2
- PMID
- 40200028
- PMCID
- PMC11978853
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Publisher
- NATURE PORTFOLIO
- Grant note
- USA National Cancer InstituteDoris Duke Charitable Foundation
USA National Cancer Institute, Doris Duke Charitable Foundation
- Language
- English
- Date published
- 04/09/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984808525702771
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