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 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, Nicholas McGranahan () and Charles Swanton ()
Additional contact information
Robert E. Hynds: University College London Cancer Institute
Ariana Huebner: University College London Cancer Institute
David R. Pearce: University College London Cancer Institute
Mark S. Hill: The Francis Crick Institute
Ayse U. Akarca: University College London Hospitals
David A. Moore: University College London Cancer Institute
Sophia Ward: University College London Cancer Institute
Kate H. C. Gowers: University College London
Takahiro Karasaki: University College London Cancer Institute
Maise Al Bakir: University College London Cancer Institute
Gareth A. Wilson: The Francis Crick Institute
Oriol Pich: University College London Cancer Institute
Carlos Martínez-Ruiz: University College London Cancer Institute
A. S. Md Mukarram Hossain: University of Manchester
Simon P. Pearce: University of Manchester
Monica Sivakumar: University College London Cancer Institute
Assma Aissa: University College London Cancer Institute
Eva Grönroos: The Francis Crick Institute
Deepak Chandrasekharan: University College London
Krishna K. Kolluri: University College London
Rebecca Towns: University College London
Kaiwen Wang: University of Leeds
Daniel E. Cook: The Francis Crick Institute
Leticia Bosshard-Carter: University College London Cancer Institute
Cristina Naceur-Lombardelli: University College London Cancer Institute
Andrew J. Rowan: The Francis Crick Institute
Selvaraju Veeriah: University College London Cancer Institute
Kevin Litchfield: University College London Cancer Institute
Philip A. J. Crosbie: University of Manchester
Caroline Dive: University of Manchester
Sergio A. Quezada: University College London Cancer Institute
Sam M. Janes: University College London
Mariam Jamal-Hanjani: University College London Cancer Institute
Teresa Marafioti: University College London Hospitals
Nicholas McGranahan: University College London Cancer Institute
Charles Swanton: University College London Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-47547-3

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