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Patient-derived xenografts undergo mouse-specific tumor evolution

Nature Genetics volume 49, pages 1567–1575 (2017)Cite this article

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Abstract

Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of preexisting minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Notably, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have major implications for PDX-based modeling of human cancer.

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Figure 1: The landscape of aneuploidy and copy number alterations in PDXs.
Figure 2: Selection of preexisting subclones underlies CNA dynamics.
Figure 3: The genomic instability of PDXs mirrors that of primary tumors.
Figure 4: Tumor evolution of PDXs diverges from that of primary tumors.
Figure 5: The genomic instability of PDXs is comparable to that of cell lines and CLDXs.
Figure 6: CNA dynamics affect PDX drug response.

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Acknowledgements

We thank L. Franke for assistance with functional genomic mRNA profiling; A. Bass, K. Ligon, A.J. Aguirre and J. Lorch for providing the clinical samples for cell line derivation; A. Tubelli for assistance with figure preparation; M. Meyerson, A.J. Cherniack, A. Taylor, A. Pearson and Z. Tothova for helpful discussions; and W.J. Gibson for copy number data. U.B.-D. is supported by a Human Frontiers Science Program postdoctoral fellowship, R.B. received support from the US National Institutes of Health (R01 CA188228) and the Gray Matters Brain Cancer Foundation, and T.R.G. received support from the Howard Hughes Medical Institute.

Author information

Author notes

  1. Rameen Beroukhim and Todd R Golub: These authors jointly directed this work.

Authors and Affiliations

  1. Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA

    Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F Greenwald, Coyin Oh, Juliann Shih, James M McFarland, Bang Wong, Jesse S Boehm, Rameen Beroukhim & Todd R Golub

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Gavin Ha & Juliann Shih

  3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Noah F Greenwald & Rameen Beroukhim

  4. Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Noah F Greenwald

  5. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Rameen Beroukhim

  6. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Rameen Beroukhim

  7. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Todd R Golub

  8. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

    Todd R Golub

  9. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Todd R Golub

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  1. Uri Ben-David
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Contributions

U.B.-D. conceived the project, collected the data and carried out the analyses. G.H., N.F.G. and J.M.M. assisted with computational analyses. Y.-Y.T. and J.S.B. provided cell line data. C.O. assisted with the copy number analysis of cell lines. B.W. assisted with figure design and preparation. J.S. assisted with the copy number analysis of TCGA samples. R.B. and T.R.G. directed the project. U.B.-D., R.B. and T.R.G. wrote the manuscript.

Corresponding authors

Correspondence to Rameen Beroukhim or Todd R Golub.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14, Supplementary Tables 1–6 and Supplementary Note (PDF 4534 kb)

Life Sciences Reporting Summary (PDF 158 kb)

Supplementary Data 1

CNA profiles of PDX samples. (XLSX 26968 kb)

Supplementary Data 2

Model-acquired CNAs in PDX samples. (XLSX 1425 kb)

Supplementary Data 3

CNA profiles of CLDX samples. (XLSX 15919 kb)

Supplementary Data 4

Model-acquired CNAs in CLDX samples. (XLSX 791 kb)

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Ben-David, U., Ha, G., Tseng, YY. et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat Genet 49, 1567–1575 (2017). https://doi.org/10.1038/ng.3967

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