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

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 () and Christian Conrad ()
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Teresa G. Krieger: Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin
Solange Le Blanc: Heidelberg University Hospital
Julia Jabs: German Cancer Research Center (DKFZ)
Foo Wei Ten: Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin
Naveed Ishaque: Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin
Katharina Jechow: Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin
Olivia Debnath: Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin
Carl-Stephan Leonhardt: Heidelberg University Hospital
Anamika Giri: German Cancer Research Center (DKFZ)
Roland Eils: Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin
Oliver Strobel: Heidelberg University Hospital
Christian Conrad: Berlin Institute of Health (BIH)/Charité-Universitätsmedizin Berlin

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26059-4

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