Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma Journal Article
| Authors: | Porter, R. L.; Magnus, N. K. C.; Thapar, V.; Morris, R.; Szabolcs, A.; Neyaz, A.; Kulkarni, A. S.; Tai, E.; Chougule, A.; Hillis, A.; Golczer, G.; Guo, H.; Yamada, T.; Kurokawa, T.; Yashaswini, C.; Ligorio, M.; Vo, K. D.; Nieman, L.; Liss, A. S.; Deshpande, V.; Lawrence, M. S.; Maheswaran, S.; Castillo, C. F. D.; Hong, T. S.; Ryan, D. P.; O'Dwyer, P. J.; Drebin, J. A.; Ferrone, C. R.; Haber, D. A.; Ting, D. T. |
| Article Title: | Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma |
| 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. © 2019 National Academy of Sciences. All rights reserved. |
| Keywords: | controlled study; protein expression; treatment response; human cell; overall survival; fluorouracil; cancer combination chemotherapy; nonhuman; mouse; mesenchyme cell; animal experiment; animal model; in vivo study; in vitro study; irinotecan; in situ hybridization; transcription regulation; folinic acid; vitamin d; western blotting; cell migration; epithelium cell; pancreas adenocarcinoma; neoadjuvant chemotherapy; oxaliplatin; vitamin d receptor; anchorage independent growth; rna sequence; pancreatic ductal adenocarcinoma; molecular subtypes; cell plasticity; gene knockdown; human; female; priority journal; article; mia paca-2 cell line; rna in situ hybridization; protein expression level; colecalciferol 24 hydroxylase; capan-2 cell line; hpaf-ii cell line; panc-1 cell line |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 116 |
| Issue: | 52 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2019-12-26 |
| Start Page: | 26835 |
| End Page: | 26845 |
| Language: | English |
| DOI: | 10.1073/pnas.1914915116 |
| PUBMED: | 31843922 |
| PROVIDER: | scopus |
| PMCID: | PMC6936349 |
| DOI/URL: | |
| Notes: | Erratum issued, see DOI: 10.1073/pnas.1922469117 -- Source: Scopus |
