Nature Communications (May 2024)
Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models
- Robert E. Hynds,
- Ariana Huebner,
- David R. Pearce,
- Mark S. Hill,
- Ayse U. Akarca,
- David A. Moore,
- Sophia Ward,
- Kate H. C. Gowers,
- Takahiro Karasaki,
- Maise Al Bakir,
- Gareth A. Wilson,
- Oriol Pich,
- Carlos Martínez-Ruiz,
- A. S. Md Mukarram Hossain,
- Simon P. Pearce,
- Monica Sivakumar,
- Assma Ben Aissa,
- Eva Grönroos,
- Deepak Chandrasekharan,
- Krishna K. Kolluri,
- Rebecca Towns,
- Kaiwen Wang,
- Daniel E. Cook,
- Leticia Bosshard-Carter,
- Cristina Naceur-Lombardelli,
- Andrew J. Rowan,
- Selvaraju Veeriah,
- Kevin Litchfield,
- Philip A. J. Crosbie,
- Caroline Dive,
- Sergio A. Quezada,
- Sam M. Janes,
- Mariam Jamal-Hanjani,
- Teresa Marafioti,
- TRACERx consortium,
- Nicholas McGranahan,
- Charles Swanton
Affiliations
- Robert E. Hynds
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Ariana Huebner
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- David R. Pearce
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Mark S. Hill
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute
- Ayse U. Akarca
- Department of Cellular Pathology, University College London Hospitals
- David A. Moore
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Sophia Ward
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Kate H. C. Gowers
- Lungs for Living Research Centre, UCL Respiratory, University College London
- Takahiro Karasaki
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Maise Al Bakir
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Gareth A. Wilson
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute
- Oriol Pich
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Carlos Martínez-Ruiz
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- A. S. Md Mukarram Hossain
- Cancer Research UK National Biomarker Centre, University of Manchester
- Simon P. Pearce
- Cancer Research UK National Biomarker Centre, University of Manchester
- Monica Sivakumar
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Assma Ben Aissa
- Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute
- Eva Grönroos
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute
- Deepak Chandrasekharan
- Lungs for Living Research Centre, UCL Respiratory, University College London
- Krishna K. Kolluri
- Lungs for Living Research Centre, UCL Respiratory, University College London
- Rebecca Towns
- Biological Services Unit, University College London
- Kaiwen Wang
- School of Medicine, University of Leeds
- Daniel E. Cook
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute
- Leticia Bosshard-Carter
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Cristina Naceur-Lombardelli
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Andrew J. Rowan
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute
- Selvaraju Veeriah
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Kevin Litchfield
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Philip A. J. Crosbie
- Cancer Research UK Lung Cancer Centre of Excellence, University of Manchester
- Caroline Dive
- Cancer Research UK National Biomarker Centre, University of Manchester
- Sergio A. Quezada
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Sam M. Janes
- Lungs for Living Research Centre, UCL Respiratory, University College London
- Mariam Jamal-Hanjani
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Teresa Marafioti
- Department of Cellular Pathology, University College London Hospitals
- TRACERx consortium
- Nicholas McGranahan
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- Charles Swanton
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute
- DOI
- https://doi.org/10.1038/s41467-024-47547-3
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 21
Abstract
Abstract Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.
