MassIVE MSV000094784

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Paracrine secretion of monounsaturated fatty acids prevents ferroptosis in triple negative breast cancer and reveals selenocysteine synthesis dependency for metastatic seeding.

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Description

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 cell death caused by iron-dependent lipid peroxidation counteracted by the antioxidant activity of selenoproteins. 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 when forming colonies from single cells. We found that the secretion of the anti-ferroptotic factor, identified as monounsaturated fatty acids (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depend on the expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of tRNAsec selenocysteinilation, an essential step for selenoproteins production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells no longer protected by the MUFA-rich environment of the primary tumour. [doi:10.25345/C53T9DJ1R] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Ferroptosis ; lipidomics ; MUFA ; selenocysteine synthesis ; fatty acids ; triple negative breast cancer

Contact

Principal Investigators:
(in alphabetical order) 		David Sumpton, CRUK Scotland Insititue, United Kingdom
Saverio Tardito, CRUK Scotland Insititue, United Kingdom
Submitting User: dsumpton

Publications

Ackermann T, Shokry E, Deshmukh R, Anand J, Galbraith LCA, Mitchell L, Rodriguez-Blanco G, Villar VH, Sterken BA, Nixon C, Zanivan S, Blyth K, Sumpton D, Tardito S.
Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.
EMBO Mol Med. 2024 Nov;16(11):2749-2774. Epub 2024 Oct 21.

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