Dataset Information

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

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 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.

INSTRUMENT(S): Q Exactive Plus, 7000A Triple Quadrupole GC/MS

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Saverio Tardito David Sumpton

PROVIDER: MSV000094784 | MassIVE | Fri May 17 02:34:00 BST 2024

REPOSITORIES: MassIVE

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

Ackermann Tobias T Shokry Engy E Deshmukh Ruhi R Anand Jayanthi J Galbraith Laura C A LCA Mitchell Louise L Rodriguez-Blanco Giovanny G Villar Victor H VH Sterken Britt Amber BA Nixon Colin C Zanivan Sara S Blyth Karen K Sumpton David D Tardito Saverio S

EMBO molecular medicine 20241021 11

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 f ...[more]

PMID: 39433871

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Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. While ferroptosis has been identified as a mechanism for suppressing cancer, its overall physiological significance remains poorly understood. Recent studies have revealed that labile iron and lipid peroxides are released from ferroptotic cells, leading to the propagation of ferroptosis through lipid peroxidation. However, other specific effects of secreted factors derived from ferroptotic cells remain unclear. We constructed a model cell system capable of inducing ferroptosis by re-expressing the transcription factor BACH1, a potent inducer of ferroptosis, in immortalized mouse embryonic fibroblasts (iMEFs). We investigated the impact of the secreted factors from ferroptotic cells with the iMEFs. As a result, we observed that the administration of supernatant media from ferroptotic iMEFs activated proliferation of hepatoma cells and suppressed cellular senescence-like features. This suggested that ferroptotic MEFs secrete anti-senescent substances. Transcriptome analysis of ferroptotic MEFs revealed an increase in the secretion of longevity factor FGF21 in a BACH1-dependent manner. Furthermore, the anti-senescent effects of the supernatant media from these ferroptotic cells were canceled by the knockout of Fgf21. Totally, it is suggested that BACH1 promotes ferroptosis in fibroblasts and contributes to the suppression of cellular senescence in neighboring cells by inducing FGF21 secretion from fibroblasts. It was also discovered that BACH1 not only activates indirectly the transcription of FGF21 by enhancing ferroptotic stress but also increases FGF21 protein level by suppressing the selective autophagic degradation of FGF21 through the transcriptional repression for Sqstm1 and Lamp2a. This represents a dual mechanism of FGF21 upregulation mediated by BACH1, suggesting that BACH1 is a potent inducer of FGF21 expression. It was also found that the BACH1-ferroptosis-FGF21 axis can suppress obesity of mice under high fat diet or short lifespan of progeria mice, closely associated phenotypes with aging. The inhibition of these aging-related phenotypes is considered to be a novel physiological significance of ferroptosis, and BACH1 is considered to function as a longevity gene by promoting ferroptotsis and subsequent FGF21 expression.