Platinum Cross-linked Collagen Matrices with Tunable Stiffness as a Platform to Investigate Cellular Mechanosensing

The mechanical properties of the cellular microenvironment are key regulators of cellular physiology. Although the field of cancer mechanobiology has attracted attention, the availability of matrix systems with independently and precisely tunable mechanical properties remains limited. Our group previously developed a collagen gel with enhanced mechanical strength by cross-linking collagen molecules using a platinum complex. In this study, we investigated the tunability of the mechanical properties of the platinum cross-linked collagen gel (PCG) and demonstrated that mechanical parameters can be controlled by varying the amount of the platinum complex. In addition, we examined how matrix mechanical properties modulate the phenotypes of lung adenocarcinoma A549 cells using the collagen matrix. Although A549 cells exhibited significant morphological alterations on stiffer matrices, these changes were not accompanied by classical epithelial-to-mesenchymal transition (EMT). Instead, they were associated with the upregulation of diverse gene expression related to cancer malignancy. We focused on maternal embryonic leucine zipper kinase (MELK) whose gene expression increased on stiffer matrices. Consistently, A549 cells cultured on stiffer matrices displayed enhanced sensitivity to a MELK-targeting anticancer drug. These findings highlight the potential of the matrices with tunable mechanical parameters not only to provide variety of physiological microenvironment but also to advance anticancer drug screening when combined with gene expression analysis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/720034v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@419074org.highwire.dtl.DTLVardef@72ef67org.highwire.dtl.DTLVardef@1c36e17org.highwire.dtl.DTLVardef@170dc33_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPlatinum cross-linked collagen gel enables independent tuning of compressive and shear elasticities. C_LIO_LICellular functions may be regulated by matrix mechanical parameters through distinct mechanisms. C_LIO_LICorrelation analysis between matrix mechanical parameters and cancer cell gene expression provides a rational strategy for therapeutic drug screening. C_LI