About our research
Our research investigates how cells sense and respond to mechanical forces within tissues, and how disruption of these processes can contribute to vascular diseases such as abdominal aortic aneurysm (AAA) and atherosclerosis, as well as cancer.
The cells of blood vessels are continuously exposed to forces generated by blood flow and pulsatile blood pressure. Endothelial cells and vascular smooth muscle cells must be able to sense these forces and convert them into biochemical signals, a process known as mechanotransduction. This is essential for maintaining the structure and function of the vessel wall. We study how mechanical forces are sensed at cell-cell junctions and what happens when this process is disrupted.
The protein AmotL2 acts as a mechanosensor in the vascular endothelium by linking the adhesion protein VE-cadherin to contractile actin filaments. We have shown that this signalling pathway regulates the inflammatory response of the vessel wall and that its disruption contributes to the development of aortic aneurysms. We are now also investigating the role of AmotL2 in vascular smooth muscle cells and in atherosclerosis.
In cancer biology, we have characterised how oxygen deprivation, or hypoxia, induces the short p60AmotL2 isoform. This isoform disrupts the apical-basal polarity of epithelial cells and weakens the connection between E-cadherin, actin filaments and the nuclear envelope. The balance between p60AmotL2 and p100AmotL2 thereby influences how readily tumour cells can detach, change shape and invade the surrounding tissue.
The group’s research is organised around two main areas: mechanotransduction and vessel wall biology, and tumour cell invasion and epithelial plasticity. We combine molecular and cell biology with preclinical models, patient-derived material and SciLifeLab’s infrastructure for high-throughput sequencing, bioinformatics and phenotypic screening.
Mechanotransduction and vessel wall biology
We investigate how AmotL2, together with VE-cadherin and the contractile actin cytoskeleton, transmits forces between endothelial cells, and how this affects vessel wall integrity and inflammatory responses. Our work includes models of abdominal aortic aneurysm and atherosclerosis. We are mapping how altered mechanotransduction in endothelial and vascular smooth muscle cells can contribute to weakening of the vessel wall and the development of atherosclerotic plaques.
Mechanical signalling extends all the way into the cell nucleus. AmotL2 links cell-cell junctions to the nuclear envelope through the actin cytoskeleton. Forces detected at these junctions can therefore alter chromatin accessibility and the activity of the epigenetic regulator EZH2, which in turn affects YAP1 expression. The response of endothelial cells to shear stress generated by blood flow depends on both AmotL2 and the signalling proteins YAP and TAZ.
Tumour cell invasion and epithelial plasticity
The p60AmotL2 isoform is induced by hypoxia and disrupts the apical-basal polarity of epithelial cells by preventing the polarity proteins Crb3 and Par3 from accumulating at the apical cell membrane. It also binds to p100AmotL2, thereby weakening the connection between E-cadherin, radial actin filaments and the nuclear envelope.
This alters both cell shape and the mechanical properties of the cell nucleus, potentially making it easier for tumour cells to squeeze through confined spaces in the extracellular matrix. We are investigating how p60AmotL2 is regulated, how the isoform affects cell-cell junctions and cell shape, and whether it can be used to identify and treat aggressive tumours. Through phenotypic screening, we are searching for vulnerabilities that are specific to tumour cells expressing p60AmotL2.
Significance and long-term aims
There is currently no established pharmacological treatment that slows the progression of abdominal aortic aneurysm. Invasive tumour growth also remains difficult to treat. Altered mechanotransduction is a shared feature of these diseases.
Our long-term aim is to understand the mechanisms linking cellular force sensing to inflammation, altered gene expression and tissue invasion. This knowledge may contribute to the development of new biomarkers and therapeutic strategies for vascular disease and cancer.
