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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
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.
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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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