Engineering cell-cell adhesion

The National Institute of General Medical Sciences awarded the University of California, Davis $672,980 on September 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859, Assistance Listing program title) to conduct research engineering cell-cell adhesion through intercellular junction mechanisms.

The research addresses the design and development of monoclonal antibodies targeting distinct cadherin conformations—strand-swap dimers and X-dimers—to engineer cell-cell adhesion and understand cadherin "outside-in" signaling pathways. The work also includes development of proximity labeling technologies triggered by protein dimerization and mechanical force to map compositional changes in desmosomes and adherens junctions in both cell culture and living organisms. The research targets applications in cancer and epithelial/endothelial barrier disease therapeutics.

Performance is located in Davis, California, with a period of performance from September 1, 2026, through April 30, 2031. The obligated amount is $672,980.

Abstract

Tissues are composed of cells that are held together in complex, three-dimensional patterns by intercellular junctions. As tissues remodel, these junctions dynamically rearrange to keep cells adherent and tissues intact. Disruptions in intercellular junctions result in several diseases including many deadly cancers, and a range of skin and heart diseases. There are two primary adhesive intercellular junctions in humans: adherens junctions (AJS) and desmosomes. The adhesive protein in both junctions are cadherins, a large family of transmembrane cell-cell adhesion proteins. The extracellular region of cadherins mechanically link cells, while their intracellular regions associate with anchoring and signaling proteins and ultimately link to the cytoskeleton. Within AJS, cadherins bind in two adhesive conformations with distinct functions: robust strand-swap dimers and weaker x-dimers. Our preliminary data demonstrates that selectively stabilizing these distinct conformations activates intracellular signaling pathways that regulate adhesion. Project 1 will rationally design monoclonal antibodies to specifically target strand-swap dimers and x-dimers to engineer cell-cell adhesion. Since cadherin adhesion defects are markers of several deadly cancers and epithelial/endothelial barrier disease, our monoclonal antibodies will have important therapeutic applications. This research will also provide fundamental insights into cadherin 'outside-in' signaling and the regulation of cell-cell adhesion. When cadherins are subjected to biochemical or mechanical cues, they change conformation and dimerize, which in turn remodels AJS and desmosomes. Project 2 will develop a suite of highly accurate proximity labeling technologies that are triggered by protein dimerization and by mechanical force. We will use these techniques to map changes in the composition of desmosomes and AJS, both in cell culture and in living organisms. These studies will provide fundamental insights into how physiological stimuli remodel adhesive structures and why this process goes awry in disease. Currently, little is known about how desmosomes assemble and respond to physiological forces. Our preliminary data establishes that desmoplakin, a key desmosomal protein, senses forces exerted on desmosomes by undergoing force-induced conformational changes. Our preliminary data also identifies crucial steps in desmosome assembly. Project 3 will unravel critical steps in desmosome formation and resolve the biophysical mechanisms by which desmosomes respond to mechanical forces. Resolving these molecular details will provide insights into desmosomal function in health and disease.