Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis
Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C.A. Galbraith, Louise Mitchell, Giovanny Rodriguez Blanco, Víctor H. Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito
Abstract
The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.