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Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease...

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Autores principales: Damayanti, Nur P., Saadatzadeh, M. Reza, Dobrota, Erika, Ordaz, Josue D., Bailey, Barbara J., Pandya, Pankita H., Bijangi-Vishehsaraei, Khadijeh, Shannon, Harlan E., Alfonso, Anthony, Coy, Kathy, Trowbridge, Melissa, Sinn, Anthony L., Zhang, Zhong-Yin, Gallagher, Rosa I., Wulfkuhle, Julia, Petricoin, Emanuel, Richardson, Angela M., Marshall, Mark S., Lion, Alex, Ferguson, Michael J., Balsara, Karl E., Pollok, Karen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244396/
https://www.ncbi.nlm.nih.gov/pubmed/37280243
http://dx.doi.org/10.1038/s41598-023-36107-2
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author Damayanti, Nur P.
Saadatzadeh, M. Reza
Dobrota, Erika
Ordaz, Josue D.
Bailey, Barbara J.
Pandya, Pankita H.
Bijangi-Vishehsaraei, Khadijeh
Shannon, Harlan E.
Alfonso, Anthony
Coy, Kathy
Trowbridge, Melissa
Sinn, Anthony L.
Zhang, Zhong-Yin
Gallagher, Rosa I.
Wulfkuhle, Julia
Petricoin, Emanuel
Richardson, Angela M.
Marshall, Mark S.
Lion, Alex
Ferguson, Michael J.
Balsara, Karl E.
Pollok, Karen E.
author_facet Damayanti, Nur P.
Saadatzadeh, M. Reza
Dobrota, Erika
Ordaz, Josue D.
Bailey, Barbara J.
Pandya, Pankita H.
Bijangi-Vishehsaraei, Khadijeh
Shannon, Harlan E.
Alfonso, Anthony
Coy, Kathy
Trowbridge, Melissa
Sinn, Anthony L.
Zhang, Zhong-Yin
Gallagher, Rosa I.
Wulfkuhle, Julia
Petricoin, Emanuel
Richardson, Angela M.
Marshall, Mark S.
Lion, Alex
Ferguson, Michael J.
Balsara, Karl E.
Pollok, Karen E.
author_sort Damayanti, Nur P.
collection PubMed
description Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson’s r = 0.794–0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4–9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient’s tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient’s resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.
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spelling pubmed-102443962023-06-08 Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion Damayanti, Nur P. Saadatzadeh, M. Reza Dobrota, Erika Ordaz, Josue D. Bailey, Barbara J. Pandya, Pankita H. Bijangi-Vishehsaraei, Khadijeh Shannon, Harlan E. Alfonso, Anthony Coy, Kathy Trowbridge, Melissa Sinn, Anthony L. Zhang, Zhong-Yin Gallagher, Rosa I. Wulfkuhle, Julia Petricoin, Emanuel Richardson, Angela M. Marshall, Mark S. Lion, Alex Ferguson, Michael J. Balsara, Karl E. Pollok, Karen E. Sci Rep Article Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson’s r = 0.794–0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4–9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient’s tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient’s resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions. Nature Publishing Group UK 2023-06-06 /pmc/articles/PMC10244396/ /pubmed/37280243 http://dx.doi.org/10.1038/s41598-023-36107-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Damayanti, Nur P.
Saadatzadeh, M. Reza
Dobrota, Erika
Ordaz, Josue D.
Bailey, Barbara J.
Pandya, Pankita H.
Bijangi-Vishehsaraei, Khadijeh
Shannon, Harlan E.
Alfonso, Anthony
Coy, Kathy
Trowbridge, Melissa
Sinn, Anthony L.
Zhang, Zhong-Yin
Gallagher, Rosa I.
Wulfkuhle, Julia
Petricoin, Emanuel
Richardson, Angela M.
Marshall, Mark S.
Lion, Alex
Ferguson, Michael J.
Balsara, Karl E.
Pollok, Karen E.
Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion
title Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion
title_full Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion
title_fullStr Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion
title_full_unstemmed Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion
title_short Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion
title_sort establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (pxa) bearing a cdc42se2-braf fusion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244396/
https://www.ncbi.nlm.nih.gov/pubmed/37280243
http://dx.doi.org/10.1038/s41598-023-36107-2
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