This project explores the role of LDL-cholesterol in integrin trafficking and signalling, which is relevant for cancer cell migration.
Cell migration is fundamental to many physiological and pathological settings such as wound healing and cancer cell metastasis. Cell migration depends on the cell surface delivery of extracellular matrix (ECM) and integrins (cell adhesion receptors composed of α and β subunits that bind to ECM). Delivery is driven by SNARE proteins, a family of small, membrane-associated proteins (e.g. Stx4, Stx6, SNAP23), that regulate transport of vesicles to the plasma membrane.
Cholesterol is an essential membrane component that determines SNARE localization and function and is indispensible for cell migration. This concept is based on artificial manipulation of cholesterol in cells. However, the lack of suitable tools to trace movement of natural cholesterol has made it impossible to put this into a physiological context. Many cancer cells accumulate large amounts of ‘bad' (Low Density Lipoprotein, LDL) cholesterol. Low ‘good' (High Density Lipoprotein, HDL) cholesterol is common in diabetic dyslipidemia and associated with impaired wound healing. Moreover, impaired LDL or HDL uptake alters cholesterol levels in the blood and its distribution in cells. However, how these cholesterol pools control SNARE localization and function in cell migration is unknown. Most cells acquire cholesterol through LDL, which is distributed along routes different from HDL or newly synthesized cholesterol. Based on our previous work, we hypothesize that LDL-cholesterol controls key events in SNARE-dependent cell migration.
Utilizing a novel fluorescent cholesterol analogue that resembles ‘good/bad' cholesterol, we are now in a unique position to elucidate a fundamental event in numerous biological processes: How, where and when do different physiological cholesterol pools alter the dynamics of the machinery that controls transport to the cell surface? This is highly relevant to link dietary/genetic/pathological changes in cholesterol metabolism with efficiency and speed of ECM and integrin cell surface delivery in wound healing and cancer cell migratio. Practical applications range from a better understanding of secretory and migratory cell behaviour upon therapeutic lowering of LDL-cholesterol, to the development of novel strategies targeting SNARE and integrin function in cancer metastasis, angiogenesis, but also autoimmune response or initiation of inflammatory response in wound healing.
The opportunity ID for this research opportunity is 1878