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: | , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
05 October 2021
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| 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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| 520 | |a 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. | ||
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