EFRI-MIKS: Force Sensing and Remodeling by Cell-Cell Junctions in Multicellular Tissues

Stanford University, Stanford CA

Investigators

Abstract

This award by the Office of Emerging Frontiers in Research and Innovation supports work to study mechanical interactions between cells that govern the basic processes of life and underpin many unresolved questions in multicellular biology. Mechanical stresses can modulate healthy and diseased cell responses such as renewal, growth, cell death or disease progression. Such mechanical signals can also directly regulate signaling pathways controlling cancer metastasis, cardiovascular remodeling or stem cell differentiation. The mechano-response of cell-cell adhesive structures to applied force is only recently documented, yet remains poorly characterized. Our inter-disciplinary team is addressing critical measurement challenges in biology to understand the cellular responses of dynamic mechanical load at cell-cell junctions. In this program, we will: 1) Develop novel engineering devices to image cell-cell junctions in living cells under dynamic applied load. These measurements will test models of cell adhesion remodeling in response to external mechanical load in multicellular tissue-like assemblies; 2) Apply innovative single-molecule assays to characterize force-dependent protein-protein interactions that are hypothesized to underlie cell adhesion remodeling; 3) Demonstrate a new class of molecular force sensors that can directly visualize the transmission of molecular-scale mechanical force through cell-cell adhesions. Our team unites an unusual combination of expertise in cell biology, structural biology, engineering, and biophysics and is well-positioned to tackle fundamental questions in mechanobiology that would be impossible for each individual research group to address alone. This work has transformative potential to revolutionize quantitative biology and unites unique views and skills in the growing, interdisciplinary field of mechanobiology. The intellectual merit of the work lies in the development of basic knowledge and new models for cell response to environmental cues. Inter- and intra-cellular responses to mechanical stimuli offer a test bed for characterizing the thresholds and mechanisms of environmental adaptation and remodeling of multicellular assemblies. The outcomes, methods, devices and probes developed for our experiments will be made available through publications, detailed specifications, and databases for other researchers. Models and results will be disseminated through our webpage, publications and seminars for researchers in the field, and public seminar forums. The broad impact of our work lies in enhancing knowledge of multicellular mechanical signaling, the role of the mechanical environment in cell behaviors, fundamental mechanisms for force and displacement sensing at the molecular scale, and the development of enhanced protocols, probes, and technologies to study the mechanobiology of multicellular systems in vivo and in vitro. Topics of our research will be incorporated in modules for teaching basic Engineering and Biology courses, and the development of undergraduate research experiences within our laboratories. The PIs actively participate in community outreach, undergraduate research opportunities, and research experience for teachers and under-represented student research programs. This award allows us to expand these efforts and include more participation to this work, as well as to showcase the work through public outreach via booths at community fairs and public talks.