Heterotypic 3D pancreatic cancer model with tunable proportion of fibrotic elements
Heterotypic 3D pancreatic cancer model with tunable proportion of fibrotic elements
复制标题
纤维化成分比例可调的异型 3D 胰腺癌模型
DOI：
10.1016/j.biomaterials.2020.120077
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发表时间：
2020
期刊：
影响因子：
14
通讯作者：
Kano Mitsunobu R.
中科院分区：
文献类型：
--
作者：
Tanaka Hiroyoshi Y.;Kurihara Tsuyoshi;Nakazawa Takuya;Matsusaki Michiya;Masamune Atsushi;Kano Mitsunobu R.
胰腺导管腺癌（PDAC）是一种以致密纤维化间质为特征的常致死性疾病。然而，缺乏相关的临床前模型来概括人类pdac玻璃体的特征组织病理学，阻碍了新疗法的发展。患者体内和患者之间基质成分的数量差异很大，但人类PDAC的体外模型通常不能解释这种异质性。事实上，人类PDAC组织病理学分析显示，患者间质比例从40%到80%不等。因此，我们生成了一个新的人类PDAC 3D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，其中纤维化元素的比例可以在临床观察范围内调整。使用该模型，我们分析了肌成纤维细胞分化的信号通路，肌成纤维细胞是PDAC中常见的成纤维细胞的一个特征亚群。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，共享的和不同的信号通路调节着这些因子的核定位。我们的新模型将有助于促进对纤维化基质形成的复杂机制的理解，以及它如何可能成为治疗目标。
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 PDACin vitroimpedes the development of novel therapies. The amount of stromal elements differ largely within and between patients, butin vitromodels 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.