Intercellular Force Transduction
by Deborah Leckband,
Reid T. Milner Professor of Chemical Sciences
Chemical and Biomolecular Engineering
Chemistry and BioEngineering
Carle Illinois College of Medicine
Innovation Grand Rounds
Friday, September 10, 2021
noon – 1:00 p.m. Presentation by Deborah Leckband
1:00 – 1:30 p.m. Reflection & Dialogue
Our work focuses on determining how force-transduction mechanisms in tissues contribute to human pathologies such as ventilator induced lung injury and malignant transformation in breast cancer and glioblastoma. Studies are investigating how cells sense mechanical changes in their environment and the impact of force-activated cascades on cell and tissue functions. Specifically, we focus on cadherins, which are essential intercellular adhesion proteins. Cadherin complexes are critical mechanical and signalling hubs that maintain the integrity of all soft tissues and regulate proliferation. Using different mechanical and biochemical tools, we identified force-activated signalling cascades at intercellular junctions that regulate cell mechanics, proliferation, and the barrier integrity of blood vessels and epithelial tissues. In epithelia, E-cadherin is a tumour suppressor that regulates epidermal growth factor receptor (EGFR) signalling. Findings revealed that increased tension on intercellular contacts (E-cadherin receptors) activates EGFR, which in turn potentiates cell proliferation. We found that force disrupts inhibitory E-cadherin/EGFR complexes to enable EGFR signaling, thus overcoming contact-inhibited cell proliferation. We are investigating the broader implications of these findings in 3D breast tumor organoid models. We further demonstrated similar cadherin force transduction mechanisms in other tissues that express different cadherin/growth factor receptor combinations. In the vascular endothelium, for example, VE-cadherin and vascular endothelial growth factor receptor similarly regulate proliferation and vascular permeability. We are using lung-on-a-chip microfluidic devices to explore mechanically activated signalling pathways that regulate vascular permeability in, for example, ventilator induced lung injury and fibrosis.
Professor Deborah Leckband is recognized internationally for pathbreaking research on the biophysical and molecular mechanisms of cell adhesion and mechano-transduction. Her lab has published numerous peer reviewed manuscripts that revealed novel biophysical mechanisms of protein-mediated cell adhesion. A major focus of her work is on translating those discoveries to tissue and stem cell engineering, pathologies such as ventilator induced lung injury, lung fibrosis, and breast cancer. Prof. Leckband’s research uses cadherins—essential cell-cell adhesion proteins—as a model system. Her research team discovered novel structure-function relationships of cadherin proteins that affect how cells assemble and maintain intercellular adhesions. They demonstrated that cadherin complexes are sites of force transduction in tissues and identified force transduction mechanisms that link tissue mechanics to cell proliferation and the integrity of barrier tissues such as the vascular endothelium. Professor Leckband has trained numerous graduate students and postdocs, several of whom are now independent faculty members at universities in the US and abroad. She has numerous national and international collaborations, including collaborations with several faculty at UIUC.