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Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma
Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with feature...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936349/ https://www.ncbi.nlm.nih.gov/pubmed/31843922 http://dx.doi.org/10.1073/pnas.1914915116 |
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author | Porter, Rebecca L. Magnus, Neelima K. C. Thapar, Vishal Morris, Robert Szabolcs, Annamaria Neyaz, Azfar Kulkarni, Anupriya S. Tai, Eric Chougule, Abhijit Hillis, Alissandra Golczer, Gabriel Guo, Hongshan Yamada, Teppei Kurokawa, Tomohiro Yashaswini, Chittampalli Ligorio, Matteo Vo, Kevin D. Nieman, Linda Liss, Andrew S. Deshpande, Vikram Lawrence, Michael S. Maheswaran, Shyamala Fernandez-Del Castillo, Carlos Hong, Theodore S. Ryan, David P. O’Dwyer, Peter J. Drebin, Jeffrey A. Ferrone, Cristina R. Haber, Daniel A. Ting, David T. |
author_facet | Porter, Rebecca L. Magnus, Neelima K. C. Thapar, Vishal Morris, Robert Szabolcs, Annamaria Neyaz, Azfar Kulkarni, Anupriya S. Tai, Eric Chougule, Abhijit Hillis, Alissandra Golczer, Gabriel Guo, Hongshan Yamada, Teppei Kurokawa, Tomohiro Yashaswini, Chittampalli Ligorio, Matteo Vo, Kevin D. Nieman, Linda Liss, Andrew S. Deshpande, Vikram Lawrence, Michael S. Maheswaran, Shyamala Fernandez-Del Castillo, Carlos Hong, Theodore S. Ryan, David P. O’Dwyer, Peter J. Drebin, Jeffrey A. Ferrone, Cristina R. Haber, Daniel A. Ting, David T. |
author_sort | Porter, Rebecca L. |
collection | PubMed |
description | Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials. |
format | Online Article Text |
id | pubmed-6936349 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-69363492019-12-31 Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma Porter, Rebecca L. Magnus, Neelima K. C. Thapar, Vishal Morris, Robert Szabolcs, Annamaria Neyaz, Azfar Kulkarni, Anupriya S. Tai, Eric Chougule, Abhijit Hillis, Alissandra Golczer, Gabriel Guo, Hongshan Yamada, Teppei Kurokawa, Tomohiro Yashaswini, Chittampalli Ligorio, Matteo Vo, Kevin D. Nieman, Linda Liss, Andrew S. Deshpande, Vikram Lawrence, Michael S. Maheswaran, Shyamala Fernandez-Del Castillo, Carlos Hong, Theodore S. Ryan, David P. O’Dwyer, Peter J. Drebin, Jeffrey A. Ferrone, Cristina R. Haber, Daniel A. Ting, David T. Proc Natl Acad Sci U S A Biological Sciences Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials. National Academy of Sciences 2019-12-26 2019-12-16 /pmc/articles/PMC6936349/ /pubmed/31843922 http://dx.doi.org/10.1073/pnas.1914915116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Porter, Rebecca L. Magnus, Neelima K. C. Thapar, Vishal Morris, Robert Szabolcs, Annamaria Neyaz, Azfar Kulkarni, Anupriya S. Tai, Eric Chougule, Abhijit Hillis, Alissandra Golczer, Gabriel Guo, Hongshan Yamada, Teppei Kurokawa, Tomohiro Yashaswini, Chittampalli Ligorio, Matteo Vo, Kevin D. Nieman, Linda Liss, Andrew S. Deshpande, Vikram Lawrence, Michael S. Maheswaran, Shyamala Fernandez-Del Castillo, Carlos Hong, Theodore S. Ryan, David P. O’Dwyer, Peter J. Drebin, Jeffrey A. Ferrone, Cristina R. Haber, Daniel A. Ting, David T. Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
title | Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
title_full | Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
title_fullStr | Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
title_full_unstemmed | Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
title_short | Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
title_sort | epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936349/ https://www.ncbi.nlm.nih.gov/pubmed/31843922 http://dx.doi.org/10.1073/pnas.1914915116 |
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