Journal article
Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution
Nature communications, Vol.13(1), pp.3652-16
06/25/2022
DOI: 10.1038/s41467-022-31376-3
PMID: 35752636
Abstract
Heterogeneity is a hallmark of cancer. The advent of single-cell technologies has helped uncover heterogeneity in a high-throughput manner in different cancers across varied contexts. Here we apply single-cell sequencing technologies to reveal inherent heterogeneity in assumptively monoclonal pancreatic cancer (PDAC) cell lines and patient-derived organoids (PDOs). Our findings reveal a high degree of both genomic and transcriptomic polyclonality in monolayer PDAC cell lines, custodial variation induced by growing apparently identical cell lines in different laboratories, and transcriptomic shifts in transitioning from 2D to 3D spheroid growth models. Our findings also call into question the validity of widely available immortalized, non-transformed pancreatic lines as contemporaneous “control” lines in experiments. We confirm these findings using a variety of independent assays, including but not limited to whole exome sequencing, single-cell copy number variation sequencing (scCNVseq), single-nuclei assay for transposase-accessible chromatin with sequencing, fluorescence in-situ hybridization, and single-cell RNA sequencing (scRNAseq). We map scRNA expression data to unique genomic clones identified by orthogonally-gathered scCNVseq data of these same PDAC cell lines. Further, while PDOs are known to reflect the cognate in vivo biology of the parental tumor, we identify transcriptomic shifts during ex vivo passage that might hamper their predictive abilities over time. The impact of these findings on rigor and reproducibility of experimental data generated using established preclinical PDAC models between and across laboratories is uncertain, but a matter of concern.
It is unclear if the molecular profiles of pancreatic ductal adenocarcinoma (PDAC) preclinical models remain stable during propagation. Here, the authors characterise clonal evolution throughout propagation in PDAC cell lines and a patient-derived organoid using single-cell genomics, transcriptomics and epigenomics.
Details
- Title: Subtitle
- Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution
- Creators
- Maria E. Monberg - The University of Texas MD Anderson Cancer CenterHeather Geiger - New York Genome CenterJaewon J. Lee - The University of Texas MD Anderson Cancer CenterRoshan Sharma - New York Genome CenterAlexander Semaan - The University of Texas MD Anderson Cancer CenterVincent Bernard - The University of Texas MD Anderson Cancer CenterJustin Wong - The University of Texas MD Anderson Cancer CenterFang Wang - The University of Texas MD Anderson Cancer CenterShaoheng Liang - The University of Texas MD Anderson Cancer CenterDaniel B. Swartzlander - The University of Texas MD Anderson Cancer CenterBret M. Stephens - The University of Texas MD Anderson Cancer CenterMatthew H. G. Katz - The University of Texas MD Anderson Cancer CenterKen Chen - The University of Texas MD Anderson Cancer CenterNicolas Robine - New York Genome CenterPaola A. Guerrero - The University of Texas MD Anderson Cancer CenterAnirban Maitra - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.13(1), pp.3652-16
- DOI
- 10.1038/s41467-022-31376-3
- PMID
- 35752636
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group UK
- Grant note
- SE-2616/2-1 / Deutsche Forschungsgemeinschaft (German Research Foundation) (https://doi.org/10.13039/501100001659) T32CA009599; U54CA096300; U54CA096297; T32CA217789; NIH U01CA196403; NIH U01CA200468; P50CA221707 / Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) (https://doi.org/10.13039/100000009)
- Language
- English
- Date published
- 06/25/2022
- Academic Unit
- Surgery
- Record Identifier
- 9985240893702771
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