Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis

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. At high density and in tumours TNBC cells produce MUFAs via SCD and secrete lipid-bound MUFAs that protects them from pro-ferroptotic lipid peroxidation. TNBC cells metastasizing in the bloodstream downregulate SCD expression that sensitizes them to the inhibition of Sec-tRNAsec biosynthesis.Selenium limitation triggers ferroptosis selectively in TNBC cells cultured at low cell density.TNBC cells cultured at high cell density secrete SCD-derived anti-ferroptotic lipid-bound MUFAs.SCD expression is regulated by cell density and is high in tumours and low in metastasizing cells.Sec-tRNAsec biosynthesis interference selectively impairs TNBCs metastasis. At high density and in tumours TNBC cells produce MUFAs via SCD and secrete lipid-bound MUFAs that protects them from pro-ferroptotic lipid peroxidation. TNBC cells metastasizing in the bloodstream downregulate SCD expression that sensitizes them to the inhibition of Sec-tRNAsec biosynthesis.