Betydelsen av interaktioner mellan endotelceller och immunceller för tumörmetastasering

Tidsperiod: 2017-01-01 till 2019-12-31

Projektledare: Michael Welsh

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 2 100 000 SEK

Metastasis is thought to involve tumor invasiveness, endothelial transmigration and the ability to seed at distant sites. Endothelial/immune cell interactions have recently been suggested to play a role in this context. SHB signals downstream of tyrosine kinase receptors, and we therefore generated a global SHB knockout mouse in which we observe effects on angiogenesis and T cell function. To specifically assess endothelial/immune cell interactions in metastasiswe will thus use a conditional SHB knockout mouse to: 1. Understand the role of SHB for vascular and hematopoietic function. 2. Understand the molecular mechanisms of melanoma metastasis in relation to vascular and immune cell function by studying these processes after conditional inactivation of the SHB gene in vascular and immune cells. Particular attention will be given to the role of endothelial cells in regulating the immune response to the tumor cells. 3. Screen for chemical inhibitors of SHB function using a low molecular weight inhibitor library including the assessment of SHB’s interactions with FAK and VEGFR2 at different subcellular sites. It is hoped that the project will produce data that increase our mechanistic understanding of tumor metastasis from a general perspective focusing on the role of the endothelium in recruiting immune cells that are anti-tumorigenic. In an extension, we hope that the knowledge may become applicable to novel treatment regimens for cancer and its metastasis.