Lena Claesson-Welsh's research projects in vascular biology

Regulation of inflammation and angiogenesis by histidine-rich glycoprotein (HRG)

The heparin-binding plasma protein HRG was originally identified as a regulator of tumour angiogenesis. We have shown in a number of models that administration of HRG or expression of HRG in tumours results in reduced primary tumour growth and reduced metastatic spread. These effects of HRG depend on polarization of macrophages from an M2 to an M1 phenotype, accompanied by reduced production of angiogenic growth factors and promotion of an anti-tumour immune response.

Current aims include to identify the HRG-binding molecule, the HRG receptor, on mononuclear phagocytes, and to explore the potential therapeutic benefit of HRG in combinatorial cancer immunotherapy.
 

Regulation of angiogenesis and vascular leakage

Dysregulation of VEGF and its receptor VEGFR2 in tumours leads to exaggerated formation of leaky and dysfunctional vessels, which in turn promotes tumour invasiveness and metastatic spread. We have identified the in vivo signal transduction pathway regulating vascular leakage in response to VEGF.

The pathway is initiated by phosphorylation of tyrosine 949 in VEGFR2, which allows binding of the Src Homology 2 (SH2) domain-containing adaptor molecule TSAd (T cell specific adaptor) that in turn couples to the cytoplasmic kinase c-Src. c-Src becomes translocated to endothelial cell junctions where it phosphorylates the important adherens junction component vascular endothelial cadherin.

Gene targeting to eliminate Y949 or TSAd specifically in endothelial cells results in a block in VEGF-induced vascular leakage and thereby reduced edema and suppressed metastatic spread in a number of mouse tumour models (melanoma, glioblastoma, insulinoma).

Drug screening is ongoing to identify a drug that blocks the Y949-TSAd-c-Src pathway. We moreover study the dynamics of the transient opening of endothelial junctions using live microscopy. In a parallel project, we examine the biology regulated by other VEGFR2 phosphotyrosine sites such as Y1212.

In the different projects, we address the role of VEGF co-receptors (heparan sulfate and neuropilin) in presentation of VEGF to VEGFR2, their ability to regulate VEGFR2 internalization and the subsequent biological response.


  
For more information about our research, protocols or potential post doc positions please contact Lena Claesson-Welsh