Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma.
Biomimetic and enzyme-responsive dynamic hydrogels for studying cell-matrix interactions in pancreatic ductal adenocarcinoma.
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DOI：
10.1016/j.biomaterials.2018.01.012
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发表时间：
2018-04
期刊：
影响因子：
14
通讯作者：
Lin CC
中科院分区：
文献类型：
--
作者：
Liu HY;Korc M;Lin CC
肿瘤微环境（TME）控制癌症进展的所有方面，并且体外3D细胞培养平台越来越多地被开发以模拟基质组织和癌细胞的组分之间的相互作用。然而，传统的细胞培养平台不足以概括TME，其具有复杂的组成和动态变化的基质力学。在这项研究中，我们开发了一个动态明胶-透明质酸杂化水凝胶系统，通过集成模块化巯基-藜芦烯光聚合和酶触发按需基质硬化。特别地，明胶用藜芦烯和4-羟基苯乙酸双重改性，以使该生物活性蛋白质可光交联（通过硫醇-藜芦烯凝胶化）并响应于酪氨酸酶触发的按需硬化（通过HPA二聚化）。除了提供基本的细胞粘附基序和蛋白酶可切割序列的改性明胶之外，透明质酸（HA）（一种必需的肿瘤基质）被模块化地和共价地并入到载有细胞的凝胶网络中。我们系统地表征了大分子单体改性、凝胶交联以及酶引发的硬化和降解。我们还评估了基质成分和动态硬化对胰腺导管腺癌（PDAC）细胞命运的影响。我们发现，无论是含HA的矩阵或动态硬化的微环境抑制PDAC细胞的生长。有趣的是，这两个因素协同诱导细胞表型的变化，类似于细胞迁移和/或入侵的3D。额外的mRNA表达阵列分析揭示了HA存在、硬化微环境或两者结合所特有的变化。最后，我们提出了免疫染色和mRNA表达数据，以证明这些不规则的PDAC细胞表型是基质诱导的上皮间质转化（EMT）的结果。
The tumor microenvironment (TME) governs all aspects of cancer progression and in vitro 3D cell culture platforms are increasingly developed to emulate the interactions between components of the stromal tissues and cancer cells. However, conventional cell culture platforms are inadequate in recapitulating the TME, which has complex compositions and dynamically changing matrix mechanics. In this study, we developed a dynamic gelatin-hyaluronic acid hybrid hydrogel system through integrating modular thiol-norbornene photopolymerization and enzyme-triggered on-demand matrix stiffening. In particular, gelatin was dually modified with norbornene and 4-hydroxyphenylacetic acid to render this bioactive protein photo-crosslinkable (through thiol-norbornene gelation) and responsive to tyrosinase-triggered on-demand stiffening (through HPA dimerization). In addition to the modified gelatin that provides basic cell adhesive motifs and protease cleavable sequences, hyaluronic acid (HA), an essential tumor matrix, was modularly and covalently incorporated into the cell-laden gel network. We systematically characterized macromer modification, gel crosslinking, as well as enzyme-triggered stiffening and degradation. We also evaluated the influence of matrix composition and dynamic stiffening on pancreatic ductal adenocarcinoma (PDAC) cell fate in 3D. We found that either HA-containing matrix or a dynamically stiffened microenvironment inhibited PDAC cell growth. Interestingly, these two factors synergistically induced cell phenotypic changes that resembled cell migration and/or invasion in 3D. Additional mRNA expression array analyses revealed changes unique to the presence of HA, to a stiffened microenvironment, or to the combination of both. Finally, we presented immunostaining and mRNA expression data to demonstrate that these irregular PDAC cell phenotypes were a result of matrix-induced epithelial-mesenchymal transition (EMT).
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影响因子：
9.7
作者：
Gore J;Imasuen-Williams IE;Conteh AM;Craven KE;Cheng M;Korc M
通讯作者：
Korc M
影响因子：
--
作者：
Jakubowska K;Pryczynicz A;Januszewska J;Sidorkiewicz I;Kemona A;Niewiński A;Lewczuk Ł;Kędra B;Guzińska-Ustymowicz K
通讯作者：
Guzińska-Ustymowicz K
影响因子：
3
作者：
Korc, Murray
通讯作者：
Korc, Murray
影响因子：
4
作者：
Castellanos JA;Merchant NB;Nagathihalli NS
通讯作者：
Nagathihalli NS
DOI：
10.1016/s0167-4838(01)00207-2
发表时间：
2001-07-09
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY
影响因子：
--
作者：
Fenoll, LG;Rodríguez-López, JN;Tudela, J
通讯作者：
Tudela, J