Tanaka Hiroyoshi Y, Kurihara Tsuyoshi, Nakazawa Takuya, Matsusaki Michiya, Masamune Atsushi, Kano Mitsunobu R
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.
Biomaterials. 2020 Aug;251:120077. doi: 10.1016/j.biomaterials.2020.120077. Epub 2020 Apr 30.
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.
胰腺导管腺癌（PDAC）是一种通常致命的疾病，其特征为存在致密的纤维化基质。然而，缺乏能够在体外重现人类PDAC特征性组织病理学的相关临床前模型，这阻碍了新型疗法的开发。基质成分的数量在患者内部和患者之间差异很大，但人类PDAC的体外模型往往没有考虑到这种异质性。事实上，对人类PDAC组织病理学的分析表明，不同患者间基质比例在40%至80%之间。因此，我们构建了一种新型的人类PDAC三维模型，该模型由共培养的人类PDAC肿瘤细胞和成纤维细胞/胰腺星状细胞组成，其中纤维化成分的比例可在临床观察到的范围内进行调节。利用该模型，我们分析了参与肌成纤维细胞分化的信号通路，肌成纤维细胞是PDAC中一种具有特征性的成纤维细胞亚群。我们发现，成纤维细胞中的YAP和SMAD2/3都是肌成纤维细胞分化所必需的，并且在这一过程中，共享和不同的信号通路都调节这些因子的核定位。我们的新型模型将有助于促进对纤维化基质形成的复杂机制以及如何对其进行治疗靶向的理解。
