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 & Christian Conrad
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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
05 October 2021 2021 |
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| Erschienen: |
05 October 2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Nature Communications - 12(2021), Artikel-ID 5826, Seite 1-13 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Krieger, Teresa G. [VerfasserIn] |
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| Links: |
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| Themen: |
Cancer genomics |
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| Anmerkungen: |
Gesehen am 23.11.2021 |
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| Umfang: |
13 |
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| doi: |
10.1038/s41467-021-26059-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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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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