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Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma

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 patien...

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Autores principales: Zhang, Huiyuan, Qi, Lin, Du, Yuchen, Huang, L. Frank, Braun, Frank K., Kogiso, Mari, Zhao, Yanling, Li, Can, Lindsay, Holly, Zhao, Sibo, Injac, Sarah G., Baxter, Patricia A., Su, Jack M., Stephan, Clifford, Keller, Charles, Heck, Kent A., Harmanci, Akdes, Harmanci, Arif O., Yang, Jianhua, Klisch, Tiemo J., Li, Xiao-Nan, Patel, Akash J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352400/
https://www.ncbi.nlm.nih.gov/pubmed/32517016
http://dx.doi.org/10.3390/cancers12061478
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author Zhang, Huiyuan
Qi, Lin
Du, Yuchen
Huang, L. Frank
Braun, Frank K.
Kogiso, Mari
Zhao, Yanling
Li, Can
Lindsay, Holly
Zhao, Sibo
Injac, Sarah G.
Baxter, Patricia A.
Su, Jack M.
Stephan, Clifford
Keller, Charles
Heck, Kent A.
Harmanci, Akdes
Harmanci, Arif O.
Yang, Jianhua
Klisch, Tiemo J.
Li, Xiao-Nan
Patel, Akash J.
author_facet Zhang, Huiyuan
Qi, Lin
Du, Yuchen
Huang, L. Frank
Braun, Frank K.
Kogiso, Mari
Zhao, Yanling
Li, Can
Lindsay, Holly
Zhao, Sibo
Injac, Sarah G.
Baxter, Patricia A.
Su, Jack M.
Stephan, Clifford
Keller, Charles
Heck, Kent A.
Harmanci, Akdes
Harmanci, Arif O.
Yang, Jianhua
Klisch, Tiemo J.
Li, Xiao-Nan
Patel, Akash J.
author_sort Zhang, Huiyuan
collection PubMed
description 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.
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spelling pubmed-73524002020-07-15 Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma Zhang, Huiyuan Qi, Lin Du, Yuchen Huang, L. Frank Braun, Frank K. Kogiso, Mari Zhao, Yanling Li, Can Lindsay, Holly Zhao, Sibo Injac, Sarah G. Baxter, Patricia A. Su, Jack M. Stephan, Clifford Keller, Charles Heck, Kent A. Harmanci, Akdes Harmanci, Arif O. Yang, Jianhua Klisch, Tiemo J. Li, Xiao-Nan Patel, Akash J. Cancers (Basel) Article 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. MDPI 2020-06-05 /pmc/articles/PMC7352400/ /pubmed/32517016 http://dx.doi.org/10.3390/cancers12061478 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Huiyuan
Qi, Lin
Du, Yuchen
Huang, L. Frank
Braun, Frank K.
Kogiso, Mari
Zhao, Yanling
Li, Can
Lindsay, Holly
Zhao, Sibo
Injac, Sarah G.
Baxter, Patricia A.
Su, Jack M.
Stephan, Clifford
Keller, Charles
Heck, Kent A.
Harmanci, Akdes
Harmanci, Arif O.
Yang, Jianhua
Klisch, Tiemo J.
Li, Xiao-Nan
Patel, Akash J.
Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma
title Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma
title_full Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma
title_fullStr Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma
title_full_unstemmed Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma
title_short Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma
title_sort patient-derived orthotopic xenograft (pdox) mouse models of primary and recurrent meningioma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352400/
https://www.ncbi.nlm.nih.gov/pubmed/32517016
http://dx.doi.org/10.3390/cancers12061478
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