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.
2021In Redox Biology, 43, p. 102006
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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 
Dassoul, Isabelle
Mazzucchelli, Gabriel  ;  Université de Liège - ULiège > Département de chimie (sciences) > Laboratoire de spectrométrie de masse (L.S.M.)
De Pauw, Edwin  ;  Université de Liège - ULiège > Département de chimie (sciences) > Chimie analytique inorganique
Bellahcene, Akeila ;  Université de Liège - ULiège > GIGA Cancer - Metastases Research Laboratory
Yoshida, Masaru
Noël, Agnès ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Sounni, Nor Eddine  ;  Université de Liège - ULiège > GIGA Cancer - Tumours and development biology
More authors (9 more) Less
 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 :
43
Pages :
102006
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Available on ORBi :
since 26 July 2021

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