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).

The YAP1 oncogene contributes to bladder cancer cell proliferation and migration by regulating the H19 long noncoding RNA

“…Our study demonstrated the association between elevated YAP1 expression and poor clinicopathologic phenotype in bladder cancer specimens and suggested that this might be a useful marker for diagnosis. In addition, YAP1 has been shown to function in different ways [23][24][25], including abrogation of contact inhibition and promotion of the epithelial-mesenchymal transition [4,26]. Accordingly, our results showed that YAP1 dramatically increased bladder cancer cell proliferation and migration in vitro.…”

The Role of Biomaterials on Cancer Stem Cell Enrichment and Behavior

“…19 For example, an enzymatically degradable polyethylene glycol hydrogels with orthogonally controlled biophysical and biochemical properties have been developed for the study of pancreatic ductal adenocarcinoma. 58 When collagen was added to the matrix (i.e. in the presence of cell attachment), there was a greater cell spreading and an up-regulation of membrane type 1-matrix metalloproteinase 1 (MT1-MMP; i.e.…”

“…58 Interestingly, irrespective of collagen presence, cells cultured in 3D matrices developed chemo-resistance, likely as a consequence of the enrichment of pancreatic CSCs that expressed high levels of CD24, sonic hedgehog (a protein that controls cell division of adult stem cells and is implicated in the development of some cancers), and VEGF. 58 Lastly, fibrous electrospun polycaprolactone scaffolds have been tested for the expansion of breast cancer cells and showed an increased proportion of CSCs. 59 Moreover, an upregulation of EMT and increased invasive capability were observed in cells cultured on fibrous scaffolds.…”

Shooting for the moon: using tissue-mimetic hydrogels to gain new insight on cancer biology and screen therapeutics

“…While tissue-engineered models of other cancers have been developed (e.g., non-small cell lung cancer, [32,33] PDAC (pancreatic ductal adenocarcinoma), [34] hepatocellular carcinoma, [35][36][37] oral squamous cell carcinoma, [38] prostate cancer, [39,40] ovarian cancer [41][42][43] ), these examples were selected to highlight the role of materials innovation in developing hydrogel-based 3D tissue-engineered models.…”