Associate Professor Thomas Grewal
Menzies Health Institute Queensland Program Seminar Series
Infectious Diseases & Immunology
Topic: Personalised Medicine in Cancer - Host: Professor Jiri Neuzil
Assoc Prof Thomas Grewal - LDL cholesterol and cancer cell mobility - insights from the Niemann Pick Type C1 mutation and the Annexin A6 scaffold protein
Epidemiological, cell and animal studies have associated hypercholesterolemia and elevated LDL-cholesterol with increased cancer risk and metastasis. We examined how LDL-cholesterol may promote cancer progression. First, using Niemann Pick Type C1 mutants that cannot export LDL-cholesterol from late endosomes (LE), integrin delivery to the cell surface, which is critical for cell motility, was inhibited. This was due to the malfunctioning of a SNARE protein, Stx6, which delivers integrins to the cell surface. Second, LDL-cholesteryl ester storage in lipid droplets (LD) has recently been described to promote PCa progression. Mechanistically, we found that AnxA6 depletion rescued NPC1 deficiency, enabling Rab7-dependent cholesterol export from LE for neutral lipid storage in LD. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between LE and the ER in NPC1 mutants lacking AnxA6. Loss of AnxA6 and increased Rab7 levels in metastatic prostate cancers suggest a scenario of increased LDL-cholesterol transfer via MCS, which could critically contribute to PCa cancer aggressiveness.
Assoc Prof Thomas Grewal graduated in Biology from the University of Cologne and did his PhD on macrophage-specific gene regulation (University of Freiburg, Germany, 1993). He then studied lipoprotein receptors during postdoctoral fellowships with Keith Stanley (Heart Research Institute, Sydney), Jean Davignon (Clinical Research Institute, Montreal, Canada) and Ulrike Beisiegel (Hamburg, Germany). In 2003, he moved his group to the Centre for Immunology (St Vincent's Hospital, Sydney) to examine how scaffolds (annexin A6) coordinate LDL-cholesterol, membrane transport and cell signaling in cancer and cardiovascular disease. He joined the Faculty of Pharmacy (University of Sydney, Australia) in 2007. Utilizing a multi-disciplinal approach involving biochemistry, molecular cell biology, and state-of-the-art microscopy, he examines how annexin scaffolds coordinate cholesterol and fatty acid transport, and how this affects the localisation/activity of signaling complexes and receptors in cell growth and cell mobility.
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