Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones

Ben Yi Tew, Christophe Legendre, Mark A. Schroeder, Tim Triche, Gerald C. Gooden, Yizhou Huang, Loren Butry, Daniel J Ma, Kyle Johnson, Rae Anne Martinez, Mariaelena Pierobon, Emanuel F. Petricoin, Joyce O'Shaughnessy, Cindy Osborne, Coya Tapia, David N. Buckley, Jennifer Glen, Mark Bernstein, Jann N. Sarkaria, Steven A. TomsBodour Salhia

Research output: Contribution to journalArticle

Abstract

Background: The dearth of relevant tumor models reflecting the heterogeneity of human central nervous system metastasis (CM) has hindered development of novel therapies. Methods: We established 39 CM patient-derived xenograft (PDX) models representing the histological spectrum, and performed phenotypic and multi-omic characterization of PDXs and their original patient tumors. PDX clonal evolution was also reconstructed using allele-specific copy number and somatic variants. Results: PDXs retained their metastatic potential, with flank-implanted PDXs forming spontaneous metastases in multiple organs, including brain, and CM subsequent to intracardiac injection. PDXs also retained the histological and molecular profiles of the original patient tumors, including retention of genomic aberrations and signaling pathways. Novel modes of clonal evolution involving rapid expansion by a minor clone were identified in 2 PDXs, including CM13, which was highly aggressive in vivo forming multiple spontaneous metastases, including to brain. These PDXs had little molecular resemblance to the patient donor tumor, including reversion to a copy number neutral genome, no shared nonsynonymous mutations, and no correlation by gene expression. Conclusions: We generated a diverse and novel repertoire of PDXs that provides a new set of tools to enhance our knowledge of CM biology and improve preclinical testing. Furthermore, our study suggests that minor clone succession may confer tumor aggressiveness and potentiate brain metastasis.

Original languageEnglish (US)
Pages (from-to)70-83
Number of pages14
JournalNeuro-oncology
Volume22
Issue number1
DOIs
StatePublished - Jan 11 2020

Keywords

  • Animal model
  • Central nervous system metastasis
  • Clonal evolution
  • Patient-derived xenograft

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Fingerprint Dive into the research topics of 'Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones'. Together they form a unique fingerprint.

  • Cite this

    Tew, B. Y., Legendre, C., Schroeder, M. A., Triche, T., Gooden, G. C., Huang, Y., Butry, L., Ma, D. J., Johnson, K., Martinez, R. A., Pierobon, M., Petricoin, E. F., O'Shaughnessy, J., Osborne, C., Tapia, C., Buckley, D. N., Glen, J., Bernstein, M., Sarkaria, J. N., ... Salhia, B. (2020). Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones. Neuro-oncology, 22(1), 70-83. https://doi.org/10.1093/neuonc/noz137