School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47907, USA.
Department of Biological Science, Purdue University, West Lafayette, IN, 47907, USA.
Small. 2020 Mar;16(10):e1905500. doi: 10.1002/smll.201905500. Epub 2020 Jan 30.
Pancreatic ductal adenocarcinoma (PDAC) is a complex, heterogeneous, and genetically unstable disease. Its tumor microenvironment (TME) is complicated by heterogeneous cancer cell populations and strong desmoplastic stroma. This complex and heterogeneous environment makes it challenging to discover and validate unique therapeutic targets. Reliable and relevant in vitro PDAC tumor models can significantly advance the understanding of the PDAC TME and may enable the discovery and validation of novel drug targets. In this study, an engineered tumor model is developed to mimic the PDAC TME. This biomimetic model, named ductal tumor-microenvironment-on-chip (dT-MOC), permits analysis and experimentation on the epithelial-mesenchymal transition (EMT) and local invasion with intratumoral heterogeneity. This dT-MOC is a microfluidic platform where a duct of murine genetically engineered pancreatic cancer cells is embedded within a collagen matrix. The cancer cells used carry two of the three mutations of KRAS, CDKN2A, and TP53, which are key driver mutations of human PDAC. The intratumoral heterogeneity is mimicked by co-culturing these cancer cells. Using the dT-MOC model, heterogeneous invasion characteristics, and response to transforming growth factor-beta1 are studied. A mechanism of EMT and local invasion caused by the interaction between heterogeneous cancer cell populations is proposed.
胰腺导管腺癌（PDAC）是一种复杂、异质且遗传不稳定的疾病。其肿瘤微环境（TME）因异质性的癌细胞群体和强烈的纤维性基质而变得复杂。这种复杂和异质的环境使得发现和验证独特的治疗靶点变得具有挑战性。可靠且相关的 PDAC 肿瘤体外模型可以显著促进对 PDAC TME 的理解，并可能有助于发现和验证新的药物靶点。在这项研究中，开发了一种工程化肿瘤模型来模拟 PDAC TME。这种仿生模型名为导管肿瘤微环境芯片（dT-MOC），允许对上皮间质转化（EMT）和肿瘤内异质性的局部浸润进行分析和实验。该 dT-MOC 是一种微流控平台，其中嵌入了一个小鼠基因工程胰腺癌细胞的导管，该导管位于胶原蛋白基质中。所使用的癌细胞携带 KRAS、CDKN2A 和 TP53 这三种关键驱动突变中的两种，这是人类 PDAC 的关键驱动突变。通过共培养这些癌细胞来模拟肿瘤内异质性。使用 dT-MOC 模型，研究了异质侵袭特征和对转化生长因子-β1 的反应。提出了由异质性癌细胞群体相互作用引起的 EMT 和局部浸润的机制。
