LXR stimulates a metabolic switch and reveals cholesterol homeostasis as a statin target in Tasmanian devil facial tumor disease.

Devil facial tumor disease (DFTD) and its lack of available therapies are propelling the Tasmanian devil population toward extinction. This study demonstrates that cholesterol homeostasis and carbohydrate energy metabolism sustain the proliferation of DFTD cells in a cell-type-dependent manner. In addition, we show that the liver-X nuclear receptor-β (LXRβ), a major cholesterol cellular sensor, and its natural ligand 24S-hydroxycholesterol promote the proliferation of DFTD cells via a metabolic switch toward aerobic glycolysis. As a proof of concept of the role of cholesterol homeostasis on DFTD proliferation, we show that atorvastatin, an FDA-approved statin-drug subtype used against human cardiovascular diseases that inhibits cholesterol synthesis, shuts down DFTD energy metabolism and prevents tumor growth in an in vivo DFTD-xenograft model. In conclusion, we show that intervention against cholesterol homeostasis and carbohydrate-dependent energy metabolism by atorvastatin constitutes a feasible biochemical treatment against DFTD, which may assist in the conservation of the Tasmanian devil. [Display omitted] • Liver-X nuclear receptor-β signaling enhances the proliferation of DFTD cells • DFTD cells depend on carbohydrate metabolism to proliferate • Maintaining cholesterol homeostasis is essential for the proliferation of DFTD cells • Atorvastatin constitutes a feasible treatment against DFTD-infected animals Devil facial tumor disease (DFTD) threatens the Tasmanian devil with extinction. Ikonomopoulou et al. investigate how the energy metabolism of DFTD cells drives tumor growth. Using in vitro and in vivo models, they characterize the impact of cholesterol homeostasis imbalance in the integrity and proliferation of DFTD cells and tumors. [ABSTRACT FROM AUTHOR]