Patient-derived orthotopic xenograft (PDOX) mouse models of primary and recurrent meningioma

Huiyuan Zhang, Lin Qi, Yuchen Du, L. Frank Huang, Frank K. Braun, Mari Kogiso, Yanling Zhao, Can Li, Holly Lindsay, Sibo Zhao, Sarah G. Injac, Patricia A. Baxter, Jack M. Su, Clifford Stephan, Charles Keller, Kent A. Heck, Akdes Harmanci, Arif O. Harmanci, Jianhua Yang, Tiemo J. KlischXiao Nan Li*, Akash J. Patel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background. Meningiomas constitute one-third of all primary brain tumors. Although typically benign, about 20% of these tumors recur despite surgery and radiation, and may ultimately prove fatal. There are currently no effective chemotherapies for meningioma. We, therefore, set out to develop patient-derived orthotopic xenograft (PDOX) mouse models of human meningioma using tumor. Method. Of nine patients, four had World Health Organization (WHO) grade I tumors, five had WHO grade II tumors, and in this second group two patients also had recurrent (WHO grade III) meningioma. We also classified the tumors according to our recently developed molecular classification system (Types A, B, and C, with C being the most aggressive). We transplanted all 11 surgical samples into the skull base of immunodeficient (SCID) mice. Only the primary and recurrent tumor cells from one patient—both molecular Type C, despite being WHO grades II and III, respectively—led to the formation of meningioma in the resulting mouse models. We characterized the xenografts by histopathology and RNA-seq and compared them with the original tumors. We performed an in vitro drug screen using 60 anti-cancer drugs followed by in vivo validation. Results. The PDOX models established from the primary and recurrent tumors from patient K29 (K29P-PDOX and K29R-PDOX, respectively) replicated the histopathology and key gene expression profiles of the original samples. Although these xenografts could not be subtransplanted, the cryopreserved primary tumor cells were able to reliably generate PDOX tumors. Drug screening in K29P and K29R tumor cell lines revealed eight compounds that were active on both tumors, including three histone deacetylase (HDAC) inhibitors. We tested the HDAC inhibitor Panobinostat in K29R-PDOX mice, and it significantly prolonged mouse survival (p < 0.05) by inducing histone H3 acetylation and apoptosis. Conclusion. Meningiomas are not very amenable to PDOX modeling, for reasons that remain unclear. Yet at least some of the most malignant tumors can be modeled, and cryopreserved primary tumor cells can create large panels of tumors that can be used for preclinical drug testing.

Original languageEnglish (US)
Article number1478
Pages (from-to)1-17
Number of pages17
JournalCancers
Volume12
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • HDAC inhibitor
  • Meningioma
  • Modelling
  • PDOX
  • Xenograft

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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