Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy.
Teresa G KriegerSolange Le BlancJulia JabsFoo Wei TenNaveed IshaqueKatharina JechowOlivia DebnathCarl-Stephan LeonhardtAnamika GiriRoland EilsOliver StrobelChristian ConradPublished in: Nature communications (2021)
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.
Keyphrases
- single cell
- rna seq
- high throughput
- liver metastases
- end stage renal disease
- poor prognosis
- gene expression
- transcription factor
- high resolution
- chronic kidney disease
- risk factors
- coronary artery disease
- ejection fraction
- stem cells
- induced apoptosis
- oxidative stress
- adverse drug
- long non coding rna
- young adults
- drug induced
- cardiovascular disease
- induced pluripotent stem cells