Cordintion of Spatial an Temporal Regulation of Integrin and EGFR Signaling
Final Report Abstract
Our work has revealed the synergy in the cell adhesion response between integrin and EGFR, in an RGD- and EGD density and concentration-dependent manner. Cell stimulation with low to intermediate doses of EGF induces adhesion activation, whereas high EGF doses suppress adhesion. The effect of immobilized EGF differs from the effect of soluble EGF above a certain EGF density. This may be because surface presentation of the EGF ligand enables (i) more precise control over ligand accessibility and density; (ii) the non-internalization of the receptor-ligand complex, hence resulting in sustained cellular stimulation; (iii) the close proximity of the EGF and RGD ligands, which may support integrin:EGFR aggregation. This also implies that EGFR may contribute to integrin signaling in the absence of ligand, however, our data indicate that this may only be the case in cells expressing very high EGFR levels. Furthermore, the study of cell adhesion on RGD-functionalized surfaces is limited to cell lines with sufficiently high levels of avb3 receptors. However, our recent development of surfaces biofunctionalized with peptidomemitics that allow for the adhesion via further integrin receptor pairs such as a5b1 enable the extension of our analyses to additional cell types. Finally, understanding how the local presentation of extracellular stimulants at controlled positions and densities affect cell behavior is a prerequisite for the development of substrates coated with specific bioactive ligands for tissue engineering. Beyond the original project proposal, we have identified a non-coding microRNA, miR-149, to be downregulated in basal-like breast cancer, inversely correlating with the tumor grade. We show that this microRNA co-regulates ErbB receptor and integrin signaling and efficiently suppresses cell migration and invasion in vitro and lung coloniziation by breast cancer cells in vivo. Our findings establish miR-149 as a clinical marker in basal-like breast cancer and have potential implications for the design of future miRNA-based therapeutics in this disease setting.
Publications
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Benzyl alcohol and block copolymer micellar lithography: a versatile route to assembling gold and in situ generated titania nanoparticles into uniform binary nanoarrays. ACS Nano. 2011 Aug 23;5(8):6355-64
Polleux J, Rasp M, Louban I, Plath N, Feldhoff A, Spatz JP
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Regulation of integrin adhesions by varying the density of substrate-bound epidermal growth factor. Biointerphases 2012 Dec;7(1-4):23
Shahal T, Geiger B, Dunlop IE, Spatz JP
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miR149 functions as a tumor suppressor by controlling breast epithelial cell migration and invasion. Cancer Res. 2014 Sep 15;74(18):5256-65
Bischoff A, Huck B, Keller B, Strotbek M, Schmid S, Boerries M, Busch H, Müller D, Olayioye MA
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A global microRNA screen identifies regulators of the ErbB receptor signaling network. Cell Commun Signal. 2015 Jan 29;13(1):5
Bischoff A, Bayerlová M, Strotbek M, Schmid S, Beissbarth T, Olayioye MA
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Nanoscale Control of Surface Immobilized BMP-2: Toward a Quantitative Assessment of BMP- Mediated Signaling Events. Nano Lett. 2015, 11;15(3):1526-34
Schwab EH, Pohl TL, Haraszti T, Schwaerzer GK, Hiepen C, Spatz JP, Knaus P, Cavalcanti-Adam EA
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Segregation versus Colocalization: Orthogonally Functionalized Binary Micropatterned Substrates regulate the Molecular Distribution in Focal Adhesions. Adv. Materials, vol 27 issue 25, July 1, 2015, Pages 3737-3747
Guasch J, Conings B, Neubauer S, Rechenmacher F, Ende K, Rolli CG, Kappel C, Schaufler V, Kessler H, Micoulet A, Boyen HG, Cavalcanti-Adam EA, Spatz JP
