Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma

Rebecca L. Porter, Neelima K.C. Magnus, Vishal Thapar, Robert Morris, Annamaria Szabolcs, Azfar Neyaz, Anupriya S. Kulkarni, Eric Tai, Abhijit Chougule, Alessandra Hillis, Gabriel Golczer, Hongshan Guo, Teppei Yamada, Tomohiro Kurokawa, Chittampalli Yashaswini, Matteo Ligorio, Kevin D. Vo, Linda Nieman, Andrew S. Liss, Vikram DeshpandeMichael S. Lawrence, Shyamala Maheswaran, Carlos Fernandez Del Castillo, Theodore S. Hong, David P. Ryan, Peter J. O'Dwyer, Jeffrey A. Drebin, Cristina R. Ferrone, Daniel A. Haber, David T. Ting

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)26835-26845
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number52
DOIs
StatePublished - Dec 26 2019
Externally publishedYes

Keywords

  • Molecular subtypes
  • Pancreatic ductal adenocarcinoma
  • Vitamin D

ASJC Scopus subject areas

  • General

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