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; Victor H Villar; Britt Amber  Sterken; Colin  Nixon; Sara  Zanivan; Karen  Blyth; David  Sumpton; Saverio  Tardito

doi:10.1038/s44321-024-00142-x

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, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2749-2774
Number of pages	26
Journal	Embo Molecular Medicine
Volume	16
Issue number	11
Early online date	21 Oct 2024
DOIs	https://doi.org/10.1038/s44321-024-00142-x
Publication status	Published - 11 Nov 2024

Keywords

Breast cancer
Ferroptosis
Lipid metabolism
Metastasis
Selenium metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ackermann , T., Shokry, E., Deshmukh, R., Anand, J., Galbraith, L. C. A., Mitchell, L., Rodriguez-Blanco, G., Villar, V. H., Sterken, B. A., Nixon, C., Zanivan, S., Blyth, K., Sumpton, D., & Tardito, S. (2024). Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis. Embo Molecular Medicine, 16(11), 2749-2774. https://doi.org/10.1038/s44321-024-00142-x

@article{2f3dd4c00d7c4eea9843e72cf9ce4c12,

title = "Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis",

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.",

keywords = "Breast cancer, Ferroptosis, Lipid metabolism, Metastasis, Selenium metabolism",

author = "Tobias Ackermann and Engy Shokry and Ruhi Deshmukh and Jayanthi Anand and Galbraith, {Laura C A} and Louise Mitchell and Giovanny Rodriguez-Blanco and Villar, {Victor H} and Sterken, {Britt Amber} and Colin Nixon and Sara Zanivan and Karen Blyth and David Sumpton and Saverio Tardito",

note = "Funding: This work was funded by Cancer Research UK core funding awarded to the CRUK Scotland Institute (grant number A31287), Stand Up to Cancer campaign for CRUK awarded to SZ (grant number A29800), Breast Cancer Now awarded to SZ (grant number 2018NovPR102), Cancer Research UK core funding awarded to KB (grant number A29799) and Cancer Research UK core funding awarded to ST (grant number A23982).",

year = "2024",

month = nov,

day = "11",

doi = "10.1038/s44321-024-00142-x",

language = "English",

volume = "16",

pages = "2749--2774",

journal = "Embo Molecular Medicine",

issn = "1757-4676",

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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 2024, 'Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis', Embo Molecular Medicine, vol. 16, no. 11, pp. 2749-2774. https://doi.org/10.1038/s44321-024-00142-x

TY - JOUR

T1 - Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis

AU - Ackermann , Tobias

AU - Shokry, Engy

AU - Deshmukh, Ruhi

AU - Anand, Jayanthi

AU - Galbraith, Laura C A

AU - Mitchell, Louise

AU - Rodriguez-Blanco, Giovanny

AU - Villar, Victor H

AU - Sterken, Britt Amber

AU - Nixon, Colin

AU - Zanivan, Sara

AU - Blyth, Karen

AU - Sumpton, David

AU - Tardito, Saverio

N1 - Funding: This work was funded by Cancer Research UK core funding awarded to the CRUK Scotland Institute (grant number A31287), Stand Up to Cancer campaign for CRUK awarded to SZ (grant number A29800), Breast Cancer Now awarded to SZ (grant number 2018NovPR102), Cancer Research UK core funding awarded to KB (grant number A29799) and Cancer Research UK core funding awarded to ST (grant number A23982).

PY - 2024/11/11

Y1 - 2024/11/11

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Ferroptosis

KW - Lipid metabolism

KW - Metastasis

KW - Selenium metabolism

U2 - 10.1038/s44321-024-00142-x

DO - 10.1038/s44321-024-00142-x

M3 - Article

SN - 1757-4676

VL - 16

SP - 2749

EP - 2774

JO - Embo Molecular Medicine

JF - Embo Molecular Medicine

IS - 11

ER -

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

Abstract

Keywords

UN SDGs

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