Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution

Maria E. Monberg (), Heather Geiger, Jaewon J. Lee, Roshan Sharma, Alexander Semaan, Vincent Bernard, Justin Wong, Fang Wang, Shaoheng Liang, Daniel B. Swartzlander, Bret M. Stephens, Matthew H. G. Katz, Ken Chen, Nicolas Robine, Paola A. Guerrero and Anirban Maitra
Additional contact information
Maria E. Monberg: The University of Texas MD Anderson Cancer Center
Heather Geiger: New York Genome Center
Jaewon J. Lee: The University of Texas MD Anderson Cancer Center
Roshan Sharma: New York Genome Center
Alexander Semaan: The University of Texas MD Anderson Cancer Center
Vincent Bernard: The University of Texas MD Anderson Cancer Center
Justin Wong: The University of Texas MD Anderson Cancer Center
Fang Wang: The University of Texas MD Anderson Cancer Center
Shaoheng Liang: The University of Texas MD Anderson Cancer Center
Daniel B. Swartzlander: The University of Texas MD Anderson Cancer Center
Bret M. Stephens: The University of Texas MD Anderson Cancer Center
Matthew H. G. Katz: The University of Texas MD Anderson Cancer Center
Ken Chen: The University of Texas MD Anderson Cancer Center
Nicolas Robine: New York Genome Center
Paola A. Guerrero: The University of Texas MD Anderson Cancer Center
Anirban Maitra: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31376-3

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