Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.

Luis, Géraldine; Godfroid, Adrien; Nishiumi, Shin; Cimino, Jonathan; Blacher, Silvia; Maquoi, Erik; Wery, Coline; Collignon, Alice; Longuespée, Rémi; MONTERORUIZ, Laetitia; Dassoul, Isabelle; Maloujahmoum, Naima; Pottier, Charles; Mazzucchelli, Gabriel; De Pauw, Edwin; Bellahcene, Akeila; Yoshida, Masaru; Noël, Agnès; Sounni, Nor Eddine

doi:10.1016/j.redox.2021.102006

Article (Scientific journals)

Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.

Luis, Géraldine; Godfroid, Adrien; Nishiumi, Shin et al.

2021 • In Redox Biology, 43, p. 102006

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https://hdl.handle.net/2268/262273

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10.1016/j.redox.2021.102006

PubMed
34030117

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Keywords :

Drug-resistance; Hypoxia; Lipid metabolism; ROS-ferroptosis; Reoxygenation; Tumor-microenvironment

Abstract :

[en] PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. METHODS: Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. RESULTS: We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. CONCLUSION: This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence.

Disciplines :

Oncology

Author, co-author :

Luis, Géraldine ^✱

Godfroid, Adrien ^✱

Nishiumi, Shin

Cimino, Jonathan

Blacher, Silvia ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology

Maquoi, Erik ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology

Wery, Coline ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology

Collignon, Alice ; Université de Liège - ULiège > GIGA Cancer - Tumours and development biology

Longuespée, Rémi ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie analytique inorganique

MONTERORUIZ, Laetitia

More authors (9 more)

^✱ These authors have contributed equally to this work.

Language :

English

Title :

Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.

Publication date :

2021

Journal title :

Redox Biology

eISSN :

2213-2317

Publisher :

Elsevier, Netherlands

Volume :

Pages :

102006

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

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since 26 July 2021

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