Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases

Abstract Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Bot...

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Autores principales:	Andrew M. Baschnagel, Saakshi Kaushik, Arda Durmaz, Steve Goldstein, Irene M. Ong, Lindsey Abel, Paul A. Clark, Zafer Gurel, Ticiana Leal, Darya Buehler, Gopal Iyer, Jacob G. Scott, Randall J. Kimple
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cf6bf8b2cb75421fa4dbf71ed4ff419a
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spelling	oai:doaj.org-article:cf6bf8b2cb75421fa4dbf71ed4ff419a2021-12-02T13:24:17ZDevelopment and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases10.1038/s41598-021-81832-12045-2322https://doaj.org/article/cf6bf8b2cb75421fa4dbf71ed4ff419a2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81832-1https://doaj.org/toc/2045-2322Abstract Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.Andrew M. BaschnagelSaakshi KaushikArda DurmazSteve GoldsteinIrene M. OngLindsey AbelPaul A. ClarkZafer GurelTiciana LealDarya BuehlerGopal IyerJacob G. ScottRandall J. KimpleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrew M. Baschnagel Saakshi Kaushik Arda Durmaz Steve Goldstein Irene M. Ong Lindsey Abel Paul A. Clark Zafer Gurel Ticiana Leal Darya Buehler Gopal Iyer Jacob G. Scott Randall J. Kimple Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases
description	Abstract Non-small cell lung cancer (NSCLC) brain metastasis cell lines and in vivo models are not widely accessible. Herein we report on a direct-from patient-derived xenograft (PDX) model system of NSCLC brain metastases with genomic annotation useful for translational and mechanistic studies. Both heterotopic and orthotopic intracranial xenografts were established and RNA and DNA sequencing was performed on patient and matching tumors. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Transcriptome and mutation analysis revealed high correlation between matched patient and PDX samples with more than more than 95% of variants detected being retained in the matched PDXs. PDXs demonstrated response to radiation, response to selumetinib in tumors harboring KRAS G12C mutations and response to savolitinib in a tumor with MET exon 14 skipping mutation. Savolitinib also demonstrated in vivo radiation enhancement in our MET exon 14 mutated PDX. Early passage cell strains showed high consistency between patient and PDX tumors. Together, these data describe a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.
format	article
author	Andrew M. Baschnagel Saakshi Kaushik Arda Durmaz Steve Goldstein Irene M. Ong Lindsey Abel Paul A. Clark Zafer Gurel Ticiana Leal Darya Buehler Gopal Iyer Jacob G. Scott Randall J. Kimple
author_facet	Andrew M. Baschnagel Saakshi Kaushik Arda Durmaz Steve Goldstein Irene M. Ong Lindsey Abel Paul A. Clark Zafer Gurel Ticiana Leal Darya Buehler Gopal Iyer Jacob G. Scott Randall J. Kimple
author_sort	Andrew M. Baschnagel
title	Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases
title_short	Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases
title_full	Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases
title_fullStr	Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases
title_full_unstemmed	Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases
title_sort	development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cf6bf8b2cb75421fa4dbf71ed4ff419a
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Development and characterization of patient-derived xenografts from non-small cell lung cancer brain metastases

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