TY - JOUR
T1 - Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma
AU - Porter, Rebecca L.
AU - Magnus, Neelima K.C.
AU - Thapar, Vishal
AU - Morris, Robert
AU - Szabolcs, Annamaria
AU - Neyaz, Azfar
AU - Kulkarni, Anupriya S.
AU - Tai, Eric
AU - Chougule, Abhijit
AU - Hillis, Alessandra
AU - Golczer, Gabriel
AU - Guo, Hongshan
AU - Yamada, Teppei
AU - Kurokawa, Tomohiro
AU - Yashaswini, Chittampalli
AU - Ligorio, Matteo
AU - Vo, Kevin D.
AU - Nieman, Linda
AU - Liss, Andrew S.
AU - Deshpande, Vikram
AU - Lawrence, Michael S.
AU - Maheswaran, Shyamala
AU - Castillo, Carlos Fernandez Del
AU - Hong, Theodore S.
AU - Ryan, David P.
AU - O'Dwyer, Peter J.
AU - Drebin, Jeffrey A.
AU - Ferrone, Cristina R.
AU - Haber, Daniel A.
AU - Ting, David T.
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/12/26
Y1 - 2019/12/26
N2 - 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.
AB - 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.
KW - Molecular subtypes
KW - Pancreatic ductal adenocarcinoma
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=85077306735&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077306735&partnerID=8YFLogxK
U2 - 10.1073/pnas.1914915116
DO - 10.1073/pnas.1914915116
M3 - Article
C2 - 31843922
AN - SCOPUS:85077306735
SN - 0027-8424
VL - 116
SP - 26835
EP - 26845
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -