Heterotypic 3D pancreatic cancer model with tunable proportion of fibrotic elements

Hiroyoshi Y Tanaka; Tsuyoshi Kurihara; Takuya Nakazawa; Michiya Matsusaki; Atsushi Masamune; Mitsunobu R Kano

doi:10.1016/j.biomaterials.2020.120077

Heterotypic 3D pancreatic cancer model with tunable proportion of fibrotic elements

Biomaterials. 2020 Apr 30:251:120077. doi: 10.1016/j.biomaterials.2020.120077. Online ahead of print.

Authors

Hiroyoshi Y Tanaka¹, Tsuyoshi Kurihara², Takuya Nakazawa¹, Michiya Matsusaki³, Atsushi Masamune⁴, Mitsunobu R Kano⁵

Affiliations

¹ Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Okayama, Japan.
² Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Okayama, Japan.
³ Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan.
⁴ Division of Gastroenterology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
⁵ Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Okayama, Japan; Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Okayama, Japan. Electronic address: mikano-tky@umin.net.

PMID: 32388166
DOI: 10.1016/j.biomaterials.2020.120077

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; Myofibroblast; Pancreatic cancer; Pancreatic stellate cell; Tumor stroma.