7th Annual Symposium
Physics of Cancer
Leipzig, Germany
October 4-6, 2016
Invited Talk
Bottom-up Engineering of Nanoscale Devices to Program Biological Materials
David Smith
Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103 Leipzig, Germany
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Biologically evolved materials are often used as inspiration in the design and development of new materials; however, the molecular toolbox provided by biological systems has been evolutionarily optimized to carry out the necessary functions of cells. The resulting inability to systematically modify such fundamental properties such as size, binding strength and valency in experimentally available model systems hinders a meticulous examination of parameter space. We circumvent these limitations using model systems and components assembled from programmable nanomaterials such as DNA and peptides.

Synthetic constructs for crosslinking actin filaments are fabricated from DNA strands which have been conjugated to different actin-binding peptides. These were shown to modulate bulk network elasticity in accordance with binding strength, concentration and size of the crosslinking construct, and can mimic certain non-canonical behaviors of crosslinked biopolymer systems. Introduction of these synthetic constructs into living cells hinders their motility, indicating a controllable slowing or suppression of their internal actin network dynamics. In invasive (mesenchymal) cancer cells, these constructs selectively inhibit the invasion of cells into a collage network in comparison to simple migration through micrometer-sized pores, also indicating an inhibitory effect on biochemical invasion processes. Indeed, in non-malignant epithelial cells that are stimulated to undergo the epithelial-to-mesenchymal transition (EMT), these constructs fully inhibit key indicators of the transition such as the formation of actin-based stress fibers. This points towards the biasing of mechanotransductive biochemical pathways, triggered by an interplay between local network stiffening and actin depolymerization dynamics, which can be programmed in an entirely deterministic manner.

A similar approach is used to engineer "synthetic antibodies" that can be used to influence cell behavior by activating receptor-mediated pathways on the cell surface. Here, we target the Ephrin A2 recpetor, which is over-expressed in certain types of cancer, yet paradoxically triggers anti-oncogenic effects in malignant cells. By linking short (12 a.a.), Ephrin-activating peptides through DNA-based scaffolds, a valency-dependent effect on binding to EphA2-expressing cells can be controlled. Furthermore, these multivalent, synthetic antibodies can be used to cause a two-fold enhancement phenotypic expression on targeted cells.
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