Postgraduate research opportunities Is the cholesterol intracellular transport pathway a potential therapeutic target for glioblastoma?

The proposed project aims to investigate the cholesterol intracellular transport pathway as a novel cancer-specific pathway of the fatal primary brain tumour glioblastoma (GBM).

GBM is a lethal brain tumour with a worldwide incidence of ~5 per 100,000 persons and <5% five-year survival. It is on the rise in many countries, making it a crucial public health issue4. GBM tumours inevitably recur due to a sub-population of radioresistant cells, glioma stem-like cells or GSCs, that have stem-like features and play a key role in treatment resistance and tumour recurrence (Bao et al. 2006; Grech et al. 2020). To improve current clinical outcomes, we need to better understand the mechanisms that underlie glioblastoma treatment resistance to develop urgently needed therapies for this cancer of unmet need.

It has been shown that GBM cells rely heavily on free, intracellular cholesterol for growth (Villa et al. 2016) and resistance to treatments such as temozolomide(Yamamoto, Sasaki, et al. 2018b; Yamamoto, Tomiyama, et al. 2018b). Since GBM reside in the brain, the most cholesterol-rich organ in the body containing 20% of total body cholesterol, it is logical to assume that an unlimited supply of cholesterol is available for GBM further supporting tumour growth and resistance. Cholesterol can be present as free cholesterol, which is biologically active and toxic in excess, and as stored cholesterol in the form of cholesteryl esters (CE), a protected pro-survival form of energy storage in cells, deposited inside lipid droplets (LD). Because cellular free cholesterol is vital and yet lethal when in excess, multiple pathways ensure its levels are tightly controlled in healthy cells. One of these mechanisms, the intracellular cholesterol transport system, regulates free cholesterol transport from late endosomes/lysosomes to other organelles. Since free cholesterol is only esterified within the endoplasmic reticulum (ER) and mitochondria, free cholesterol trafficking and transport to these organelles is essential to maintain cholesterol homeostasis and limit free cholesterol toxic effects. Thus, we hypothesize that targeting free cholesterol transport to the ER or mitochondria has the potential to be an effective therapeutic strategy for GBM.

Our preliminary data support this hypothesis: using a 3D GBM in vitro model that exhibits key clinical features, including clinical responses to therapy (Gomez-Roman et al., 2017), we have observed a cytotoxic effect of the free cholesterol transport inhibitor U18666A. This compound selectively targets the Niemann-Pick C1 (NPC1), a lysosomal protein that transports free cholesterol derived from low-density lipoproteins extracellular uptake to the ER. U18666A treatment effectively blocks free cholesterol transport from the LE/LY to the ER leading to free cholesterol accumulation within LE/LY. intracellular cholesterol transport has also been shown to be critical for GBM survival and temozolomide therapy resistance(Yamamoto, Sasaki, et al. 2018b; Yamamoto, Tomiyama, et al. 2018b). Abnormal cholesterol transport and transport from late endosomes/lysosomes to plasma membrane has also been linked to inhibition of GBM proliferation and induction of cell death(Liu et al. 2014). Consistent with this, temozolomide resistance can be overridden by cholesterol depletion(Yamamoto, Tomiyama, et al. 2018a). We have also identified a cholesterol intracellular transport gene signature in GBM that correlates with worse prognosis. These findings effectively suggest that the cholesterol transport pathway may well be a potential therapeutic strategy for GBM.

Further information

Fully-funded students, Joint supervision will be considered with suitable partner institutions, PhD plus.