title: Thiol-ene hydrogels as desmoplasia-mimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance.
abstract: The development of pancreatic ductal adenocarcinoma (PDAC) is heavily influenced by local stromal tissues, or desmoplasia. Biomimetic hydrogels capable of mimicking tumor niches are particularly useful for discovering the role of independent matrix cues on cancer cell development. Here, we report a photo-curable and bio-orthogonal thiol-ene (i.e., cross-linked by mutually reactive norbornene and thiol groups via photoinitiation) hydrogel platform for studying the growth, morphogenesis, drug resistance, and cancer stem cell marker expression in PDAC cells cultured in 3D. The hydrogels were prepared from multi-arm poly(ethylene glycol)-norbornene cross-linked with protease-sensitive peptide to permit cell-mediated matrix remodeling. Collagen 1 fibrils were incorporated into the covalent network while cytokines (e.g., EGF and TGF-β1) were supplemented in the culture media for controlling cell fate. We found that the presence of collagen 1 enhanced cell proliferation and Yes-associated protein (YAP) translocation to cell nuclei. Cytokines and collagen 1 synergistically up-regulated MT1-MMP expression and induced cell spreading, suggestive of epithelial-mesenchymal transition (EMT) in the encapsulated cells. Furthermore, PDAC cells cultured in 3D developed chemo-resistance even in the absence of collagen 1 and cytokines. This phenotype is likely a consequence of the enrichment of pancreatic cancer stem cells that expressed high levels of CD24, sonic hedgehog (SHH), and vascular endothelial growth factor (VEGF).
authors.affiliation: Department of Biomedical Engineering, Purdue School of Engineering and Technology, Indianapolis University-Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Biosystems and Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Department of Biomedical Engineering, Purdue School of Engineering and Technology, Indianapolis University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Department of Medicine and Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and the Center for Pancreatic Cancer Research, Indianapolis, IN 46202, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
authors.affiliation: Department of Biomedical Engineering, Purdue School of Engineering and Technology, Indianapolis University-Purdue University Indianapolis, Indianapolis, IN 46202, USA. Electronic address: lincc@iupui.edu.
authors.forename: Chien-Chi
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D040761:Biomimetic Materials / Q000737:chemistry*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology*; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D009361:Neoplasm Invasiveness / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D020100:Hydrogels; D013438:Sulfhydryl Compounds
keywords: Chemo-resistance; Epithelial-mesenchymal transition; Hydrogel; Pancreatic cancer stem cell; Pancreatic ductal adenocarcinoma