Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers

Abstract Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and...

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Autores principales:	Nhu-An Pham, Nikolina Radulovich, Emin Ibrahimov, Sebastiao N. Martins-Filho, Quan Li, Melania Pintilie, Jessica Weiss, Vibha Raghavan, Michael Cabanero, Robert E. Denroche, Julie M. Wilson, Cristiane Metran-Nascente, Ayelet Borgida, Shawn Hutchinson, Anna Dodd, Michael Begora, Dianne Chadwick, Stefano Serra, Jennifer J. Knox, Steven Gallinger, David W. Hedley, Lakshmi Muthuswamy, Ming-Sound Tsao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a748f950b73d4012ad6cf5ca93a0e308
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spelling	oai:doaj.org-article:a748f950b73d4012ad6cf5ca93a0e3082021-12-02T15:45:21ZPatient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers10.1038/s41598-021-90049-12045-2322https://doaj.org/article/a748f950b73d4012ad6cf5ca93a0e3082021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90049-1https://doaj.org/toc/2045-2322Abstract Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169). KRAS mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRAS-MAPK in PDXs was independent of KRAS mutational status. Four wild-type KRAS models were characterized by one with EGFR (L747-P753 del), two with BRAF alterations (N486_P490del or V600E), and one with triple negative KRAS/EGFR/BRAF. Model OCIP256, characterized by BRAF (N486-P490 del), had activated phospho-ERK. A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies.Nhu-An PhamNikolina RadulovichEmin IbrahimovSebastiao N. Martins-FilhoQuan LiMelania PintilieJessica WeissVibha RaghavanMichael CabaneroRobert E. DenrocheJulie M. WilsonCristiane Metran-NascenteAyelet BorgidaShawn HutchinsonAnna DoddMichael BegoraDianne ChadwickStefano SerraJennifer J. KnoxSteven GallingerDavid W. HedleyLakshmi MuthuswamyMing-Sound TsaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nhu-An Pham Nikolina Radulovich Emin Ibrahimov Sebastiao N. Martins-Filho Quan Li Melania Pintilie Jessica Weiss Vibha Raghavan Michael Cabanero Robert E. Denroche Julie M. Wilson Cristiane Metran-Nascente Ayelet Borgida Shawn Hutchinson Anna Dodd Michael Begora Dianne Chadwick Stefano Serra Jennifer J. Knox Steven Gallinger David W. Hedley Lakshmi Muthuswamy Ming-Sound Tsao Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
description	Abstract Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169). KRAS mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRAS-MAPK in PDXs was independent of KRAS mutational status. Four wild-type KRAS models were characterized by one with EGFR (L747-P753 del), two with BRAF alterations (N486_P490del or V600E), and one with triple negative KRAS/EGFR/BRAF. Model OCIP256, characterized by BRAF (N486-P490 del), had activated phospho-ERK. A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies.
format	article
author	Nhu-An Pham Nikolina Radulovich Emin Ibrahimov Sebastiao N. Martins-Filho Quan Li Melania Pintilie Jessica Weiss Vibha Raghavan Michael Cabanero Robert E. Denroche Julie M. Wilson Cristiane Metran-Nascente Ayelet Borgida Shawn Hutchinson Anna Dodd Michael Begora Dianne Chadwick Stefano Serra Jennifer J. Knox Steven Gallinger David W. Hedley Lakshmi Muthuswamy Ming-Sound Tsao
author_facet	Nhu-An Pham Nikolina Radulovich Emin Ibrahimov Sebastiao N. Martins-Filho Quan Li Melania Pintilie Jessica Weiss Vibha Raghavan Michael Cabanero Robert E. Denroche Julie M. Wilson Cristiane Metran-Nascente Ayelet Borgida Shawn Hutchinson Anna Dodd Michael Begora Dianne Chadwick Stefano Serra Jennifer J. Knox Steven Gallinger David W. Hedley Lakshmi Muthuswamy Ming-Sound Tsao
author_sort	Nhu-An Pham
title	Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
title_short	Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
title_full	Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
title_fullStr	Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
title_full_unstemmed	Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
title_sort	patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a748f950b73d4012ad6cf5ca93a0e308
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Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers

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