A Synthetic Matrix with Independently Tunable Biochemistry and Mechanical Properties to Study Epithelial Morphogenesis and EMT in a Lung Adenocarcinoma Model

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dc.citation.firstpage6013en_US
dc.citation.issueNumber22en_US
dc.citation.journalTitleCancer Researchen_US
dc.citation.lastpage6023en_US
dc.citation.volumeNumber72en_US
dc.contributor.authorGill, Bartley J.en_US
dc.contributor.authorGibbons, Don L.en_US
dc.contributor.authorRoudsari, Laila C.en_US
dc.contributor.authorSaik, Jennifer E.en_US
dc.contributor.authorRizvi, Zain H.en_US
dc.contributor.authorRoybal, Jonathon D.en_US
dc.contributor.authorKurie, Jonathan M.en_US
dc.contributor.authorWest, Jennifer L.en_US
dc.contributor.orgBioengineeringen_US
dc.date.accessioned2013-08-22T22:13:43Zen_US
dc.date.available2013-08-22T22:13:43Zen_US
dc.date.issued2012en_US
dc.description.abstractBetter understanding of the biophysical and biochemical cues of the tumor extracellular matrix environment that influence metastasis may have important implications for new cancer therapeutics. Initial exploration into this question has used naturally derived protein matrices that suffer from variability, poor control over matrix biochemistry, and inability to modify the matrix biochemistry and mechanics. Here, we report the use of a synthetic polymer-based scaffold composed primarily of poly(ethylene glycol), or PEG, modified with bioactive peptides to study murine models of lung adenocarcinoma. In this study, we focus on matrix-derived influences on epithelial morphogenesis of a metastatic cell line (344SQ) that harbors mutations in Kras and p53 (trp53) and is prone to a microRNA-200 (miR-200)–dependent epithelial–mesenchymal transition (EMT) and metastasis. The modified PEG hydrogels feature biospecific cell adhesion and cell-mediated proteolytic degradation with independently adjustable matrix stiffness. 344SQ encapsulated in bioactive peptide-modified, matrix metalloproteinase–degradable PEG hydrogels formed lumenized epithelial spheres comparable to that seen with three-dimensional culture in Matrigel. Altering both matrix stiffness and the concentration of cell-adhesive ligand significantly influenced epithelial morphogenesis as manifest by differences in the extent of lumenization, in patterns of intrasphere apoptosis and proliferation, and in expression of epithelial polarity markers. Regardless of matrix composition, exposure to TGF-β induced a loss of epithelial morphologic features, shift in expression of EMT marker genes, and decrease in mir-200 levels consistent with EMT. Our findings help illuminate matrix-derived cues that influence epithelial morphogenesis and highlight the potential utility that this synthetic matrix-mimetic tool has for cancer biology.en_US
dc.embargo.termsnoneen_US
dc.identifier.citationGill, Bartley J., Gibbons, Don L., Roudsari, Laila C., et al.. "A Synthetic Matrix with Independently Tunable Biochemistry and Mechanical Properties to Study Epithelial Morphogenesis and EMT in a Lung Adenocarcinoma Model." <i>Cancer Research,</i> 72, no. 22 (2012) American Association for Cancer Research: 6013-6023. http://dx.doi.org/10.1158/0008-5472.CAN-12-0895.en_US
dc.identifier.doihttp://dx.doi.org/10.1158/0008-5472.CAN-12-0895en_US
dc.identifier.urihttps://hdl.handle.net/1911/71760en_US
dc.language.isoengen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Association for Cancer Research.en_US
dc.titleA Synthetic Matrix with Independently Tunable Biochemistry and Mechanical Properties to Study Epithelial Morphogenesis and EMT in a Lung Adenocarcinoma Modelen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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