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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030
All tumors were classified as PDAC based on histological assessment
Patient-derived PDAC organoids, as well as nine of the biopsy samples, were classified based on bulk RNA sequencing as either basal-like or classical PDAC according to the subtypes defined by Moffitt et al.[14]; in each case, the PDAC organoid subtype corresponded to the biopsy sample subtype (“Methods” and Supplementary Table 1)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Large-scale genomic studies have identified recurrent genetic alterations in PDAC, with KRAS driver mutations detected in over 90% and inactivating mutations or deletions of TP53, SMAD4, and CDKN2A in over 50% of tumors[6,7,8,9]. These alterations converge onto a limited number of aberrant signaling pathways[10,11]. The ‘classical’ subtype is associated with a higher level of mucinous features in histopathological assessment and longer survival[14] Whether these subtypes reflect genetically distinct cells, different evolutionary pathways, or different progression status, remains unclear. Evidence from multi-region-sampled metastatic pancreatic cancers suggests that basal-like cell populations may emerge as a subclonal population within classical PDAC tumors[17]
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