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ID 59946
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Tanaka, Hiroyoshi Y. Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Kurihara, Tsuyoshi Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University
Nakazawa, Takuya Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Matsusaki, Michiya Department of Applied Chemistry, Graduate School of Engineering, Osaka University
Masamune, Atsushi Division of Gastroenterology, Graduate School of Medicine, Tohoku University
Kano, Mitsunobu R. Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University ORCID Kaken ID researchmap
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an often lethal disease characterized by a dense, fibrotic stroma. However, the lack of relevant preclinical models that recapitulate the characteristic histopathology of human PDAC in vitro impedes the development of novel therapies. The amount of stromal elements differ largely within and between patients, but in vitro models of human PDAC often do not account for this heterogeneity. Indeed, analyses of human PDAC histopathology revealed that the proportion of stroma ranged from 40 to 80% across patients. We, therefore, generated a novel 3D model of human PDAC, consisting of co-cultured human PDAC tumor cells and fibroblasts/pancreatic stellate cells, in which the proportion of fibrotic elements can be tuned across the clinically observed range. Using this model, we analyzed the signaling pathways involved in the differentiation of myofibroblasts, a characteristic subpopulation of fibroblasts seen in PDAC. We show that both YAP and SMAD2/3 in fibroblasts are required for myofibroblastic differentiation and that both shared and distinct signaling pathways regulate the nuclear localization of these factors during this process. Our novel model will be useful in promoting the understanding of the complex mechanisms by which the fibrotic stroma develops and how it might be therapeutically targeted.
Keywords
3D culture
Cancer-associated fibroblast
Pancreatic stellate cell
Tumor stroma
Pancreatic cancer
Myofibroblast
Note
©2021 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 License. http://creativecommons.org/licenses/by-nc-nd/4.0/. This is the accepted manuscript version. The formal published version is available at [https://doi.org/10.1016/j.biomaterials.2020.120077] .
Published Date
2020-04-30
Publication Title
Biomaterials
Volume
volume251
Publisher
Elsevier
Start Page
120077
ISSN
0142-9612
NCID
AA00110092
Content Type
Journal Article
language
English
OAI-PMH Set
岡山大学
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DOI
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isVersionOf https://doi.org/10.1016/j.biomaterials.2020.120077
License
https://creativecommons.org/licenses/by-nc-nd/4.0/
Funder Name
Ministry of Education, Culture, Sports, Science and Technology
助成番号
20K16989
17H02099
19H03631
26293119
18H02797