Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma
| Autor: | Carlos Fernandez-del Castillo, Teppei Yamada, Linda T. Nieman, Chittampalli Yashaswini, Shyamala Maheswaran, Rebecca L. Porter, Vishal Thapar, Daniel A. Haber, Jeffrey A. Drebin, Gabriel Golczer, David P. Ryan, Michael S. Lawrence, David T. Ting, Tomohiro Kurokawa, Cristina R. Ferrone, Kevin D. Vo, Peter J. O'Dwyer, Alessandra Hillis, Annamaria Szabolcs, Anupriya S. Kulkarni, Abhijit Chougule, Theodore S. Hong, Robert Morris, Andrew S. Liss, Hongshan Guo, Neelima K.C. Magnus, Vikram Deshpande, Azfar Neyaz, Eric Tai, Matteo Ligorio |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Multidisciplinary Pancreatic ductal adenocarcinoma endocrine system diseases FOLFIRINOX Cell Mesenchymal stem cell Correction Combination chemotherapy In situ hybridization Biology Phenotype digestive system diseases 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure In vivo 030220 oncology & carcinogenesis medicine Cancer research 030304 developmental biology |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:26835-26845 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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