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Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy

Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished ‘classical’ from ‘basal-like’ tumors with more aggressive clinical behavior. We derive PDAC organoids from 18 primary tumors and two matche...

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Main Authors: Krieger, Teresa G. (Author) , Le Blanc, Solange (Author) , Jabs, Julia (Author) , Ten, Foo Wei (Author) , Ishaque, Naveed (Author) , Jechow, Katharina (Author) , Debnath, Olivia (Author) , Leonhardt, Carl-Stephan (Author) , Giri, Anamika (Author) , Eils, Roland (Author) , Strobel, Oliver (Author) , Conrad, Christian (Author)
Format: Article (Journal)
Language:English
Published: 05 October 2021
In: Nature Communications
Year: 2021, Volume: 12, Pages: 1-13
ISSN:2041-1723
DOI:10.1038/s41467-021-26059-4
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-021-26059-4
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-021-26059-4
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Author Notes:Teresa G. Krieger, Solange Le Blanc, Julia Jabs, Foo Wei Ten, Naveed Ishaque, Katharina Jechow, Olivia Debnath, Carl-Stephan Leonhardt, Anamika Giri, Roland Eils, Oliver Strobel & Christian Conrad
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Summary:Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished ‘classical’ from ‘basal-like’ tumors with more aggressive clinical behavior. We derive PDAC organoids from 18 primary tumors and two matched liver metastases, and show that ‘classical’ and ‘basal-like’ cells coexist in individual organoids. By single-cell transcriptome analysis of PDAC organoids and primary PDAC, we identify distinct tumor cell states shared across patients, including a cycling progenitor cell state and a differentiated secretory state. Cell states are connected by a differentiation hierarchy, with ‘classical’ cells concentrated at the endpoint. In an imaging-based drug screen, expression of ‘classical’ subtype genes correlates with better drug response. Our results thus uncover a functional hierarchy of PDAC cell states linked to transcriptional tumor subtypes, and support the use of PDAC organoids as a clinically relevant model for in vitro studies of tumor heterogeneity.
Item Description:Gesehen am 23.11.2021
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-021-26059-4

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