Thiol-ene hydrogels as desmoplasia-mimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance

Chang Seok Ki, Tsai Yu Lin, Murray Korc, Chien Chi Lin

Research output: Contribution to journalArticle

35 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)9668-9677
Number of pages10
JournalBiomaterials
Volume35
Issue number36
DOIs
StatePublished - 2014

Fingerprint

Hydrogels
Cell growth
Pancreatic Neoplasms
Drug Resistance
Sulfhydryl Compounds
Collagen
Cytokines
Growth
Stem cells
Adenocarcinoma
Pharmaceutical Preparations
Neoplastic Stem Cells
Cells
Matrix Metalloproteinase 14
Cultured Cells
Hydrogel
Cell proliferation
Biomimetics
Epidermal Growth Factor
Epithelial-Mesenchymal Transition

Keywords

  • Chemo-resistance
  • Epithelial-mesenchymal transition
  • Hydrogel
  • Pancreatic cancer stem cell
  • Pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics
  • Medicine(all)

Cite this

Thiol-ene hydrogels as desmoplasia-mimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance. / Ki, Chang Seok; Lin, Tsai Yu; Korc, Murray; Lin, Chien Chi.

In: Biomaterials, Vol. 35, No. 36, 2014, p. 9668-9677.

Research output: Contribution to journalArticle

Ki, Chang Seok ; Lin, Tsai Yu ; Korc, Murray ; Lin, Chien Chi. / Thiol-ene hydrogels as desmoplasia-mimetic matrices for modeling pancreatic cancer cell growth, invasion, and drug resistance. In: Biomaterials. 2014 ; Vol. 35, No. 36. pp. 9668-9677.
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AB - 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).

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