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 - Funding Information:
ACKNOWLEDGMENTS. We thank Emily Silva and Danielle Bestoso for administrative support and Drs. Joseph Franses, Julia Philipp, and Mihir Rajurkar for helpful scientific discussions. This work was supported by the Warshaw Institute for Pancreatic Cancer Research (R.L.P.); NSF Grant PHY-1549535 (D.T.T., P.J.O., J.A.D.); Stand Up To Cancer (SU2C) and Lustgarten Foundation (D.T.T., P.J.O., J.A.D., T.S.H., D.P.R.); NIH grant 2R01CA129933 (D.A.H.), Howard Hughes Medical Institute (D.A.H.); National Foundation for Cancer Research (D.A.H.); and Advanced Cell Diagnostics/Biotechne (D.T.T., A.N., A.C., A.S.K., V.D.).
Funding Information:
Competing interest statement: D.T.T. has received consulting fees from EMD Millipore-Sigma, Ventana-Roche, Foundation Medicine, Inc., and Merrimack Pharmaceuticals. D.T.T. is a founder and has equity in PanTher Therapeutics, ROME Therapeutics, and TellBio Inc., which are not related to this work. D.A.H. is founder and has equity in TellBio Inc., which is not related to this work. D.T.T.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. D.T.T. and V.D. receive sponsored research support from ACD-Biotechne that was performed for some parts of this work. V.D. receives sponsored research support from Agios. M.S.L. and E.A.C. are coauthors on a 2016 paper. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Data deposition: The data reported in this paper have been deposited in the National Center for Biotechnology Gene Expression Omnibus database, https://www.ncbi.nlm.nih. gov/geo/ (accession no. GSE141116). 1C.R.F., D.A.H., and D.T.T. contributed equally to this work. 2To whom correspondence may be addressed. Email: dhaber@mgh.harvard.edu or dting1@mgh.harvard.edu. This article contains supporting information online at https://www.pnas.org/lookup/suppl/ doi:10.1073/pnas.1914915116/-/DCSupplemental. First published December 16, 2019.
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
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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 -