Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy
Teresa Gabriela Krieger,
Foo Wei Ten,
Posted 24 Aug 2020
bioRxiv DOI: 10.1101/2020.08.23.263160
Posted 24 Aug 2020
Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished 'classical' pancreatic tumors from 'basal-like' tumors with more aggressive clinical behaviour. We derived PDAC organoids from primary tumors of 18 patients, together with two matched samples from liver metastases. By single-cell RNA sequencing, we show that PDAC organoids consist of ductal cells with patient-specific expression of several gene groups, including genes which encode cell surface proteins. We report 'classical' and 'basal-like' cells coexisting within single primary tumors or metastases, with greater intratumor subtype heterogeneity linked to higher tumor grade. Single-cell transcriptome analysis of PDAC organoids and primary PDAC identified distinct tumor cell states shared across patients, including a cycling progenitor cell state and a differentiated secretory state. We show that these cell states are connected by a differentiation hierarchy, with 'classical' subtype cells concentrated at the endpoint of this hierarchy. In an imaging-based drug screen, expression of 'classical' subtype genes also correlates with better response to clinical drugs. 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. ### Competing Interest Statement The authors have declared no competing interest.
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