Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma
Open accessAbstract
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.
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Ting and colleagues have shown evidence of subtype "drift" in PDAC tissues with various therapies.
“Of note, a recent assessment for “basal-like” and “classical” cells in PDAC tissues by subtype-specific protein markers has uncovered bi-phenotypic “hybrid” cells51, while Ting and colleagues have shown evidence of subtype “drift” in PDAC tissues with various therapies52, both lines of evidence supporting the plasticity of subtype states.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as [52]
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- 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., Fernandez-Del Castillo, C., Hong, T. S., Ryan, D. P., O’Dwyer, P. J., Drebin, J. A., Ferrone, C. R., Haber, D. A., & Ting, D. T.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114;
- Broad Institute (US)
- Department of Surgery, Harvard Medical School, Boston, MA 02114;
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19014;
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Haber, Daniel A.
- Ting, David T.
- ORCID
- Porter, Rebecca L.
- Thapar, Vishal
- Morris, Robert
- Neyaz, Azfar
- Kulkarni, Anupriya S.
- Golczer, Gabriel
- Guo, Hongshan
- Yamada, Teppei
- Kurokawa, Tomohiro
- Yashaswini, Chittampalli
- Ligorio, Matteo
- Nieman, Linda
- Liss, Andrew S.
- Deshpande, Vikram
- Lawrence, Michael S.
- Maheswaran, Shyamala
- Hong, Theodore S.
- Ryan, David P.
- Drebin, Jeffrey A.
- Ferrone, Cristina R.
- Haber, Daniel A.
- Ting, David T.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-12-16
- Volume
- 116
- Issue
- 52
- Pages
- 26835-26845
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6936349
- OpenAlex
- W2995007557
- Cited by
- 129
- References
- 35
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 25 · 2023: 18 · 2022: 20 · 2021: 25 · 2020: 9
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-01-13)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- EIF | Stand Up To Cancer (2015-002)
- Lustgarten Foundation (2015-002)
- Warshaw Institute (N/A)
- National Science Foundation (PHY-1549535)
- ACD-Biotechne (N/A)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- pancreatic ductal adenocarcinoma, epithelial-mesenchymal plasticity, epithelial-mesenchymal transition, tumor subtypes, FOLFIRINOX, vitamin D, treatment response, metastasis, gene expression profiling, drug response
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