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

Géraldine Luis; Adrien Godfroid; Shin Nishiumi; Jonathan Cimino; Silvia Blacher; Erik Maquoi; Coline Wery; Alice Collignon; Rémi Longuespée; Laetitia Montero-Ruiz; Isabelle Dassoul; Naima Maloujahmoum; Charles Pottier; Gabriel Mazzucchelli; Edwin Depauw; Akeila Bellahcène; Masaru Yoshida; Agnès Noel; Nor Eddine Sounni

doi:10.1016/j.redox.2021.102006

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

Redox Biol. 2021 Jul:43:102006. doi: 10.1016/j.redox.2021.102006. Epub 2021 May 14.

Authors

Géraldine Luis¹, Adrien Godfroid², Shin Nishiumi³, Jonathan Cimino⁴, Silvia Blacher⁵, Erik Maquoi⁵, Coline Wery⁶, Alice Collignon⁶, Rémi Longuespée⁷, Laetitia Montero-Ruiz⁶, Isabelle Dassoul⁵, Naima Maloujahmoum⁸, Charles Pottier⁶, Gabriel Mazzucchelli⁹, Edwin Depauw⁹, Akeila Bellahcène⁸, Masaru Yoshida¹⁰, Agnès Noel⁵, Nor Eddine Sounni¹¹

Affiliations

¹ Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium; Cancer Metabolism and Tumor Microenvironment Group, GIGA Cancer, Liège University, Liège, Belgium. Electronic address: geraldine.luis@chuliege.be.
² Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium; Cancer Metabolism and Tumor Microenvironment Group, GIGA Cancer, Liège University, Liège, Belgium. Electronic address: adrien.godfroid@outlook.be.
³ Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Omics Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
⁴ Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium; Mass Spectrometry Laboratory, MolSys Research Unit, University of Liège, Liège, Belgium; Clinical Research Unit, Fondation Hôpitaux Robert Schuman, Hôpitaux Robert Schuman, Luxembourg.
⁵ Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium.
⁶ Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium; Cancer Metabolism and Tumor Microenvironment Group, GIGA Cancer, Liège University, Liège, Belgium.
⁷ Mass Spectrometry Laboratory, MolSys Research Unit, University of Liège, Liège, Belgium; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
⁸ Metastasis Research Laboratory, GIGA Cancer, University of Liège, 4000, Liège, Belgium.
⁹ Mass Spectrometry Laboratory, MolSys Research Unit, University of Liège, Liège, Belgium.
¹⁰ Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Metabolomics Research, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan; AMED-CREST, AMED, Kobe, Japan.
¹¹ Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium; Cancer Metabolism and Tumor Microenvironment Group, GIGA Cancer, Liège University, Liège, Belgium. Electronic address: nesounni@uliege.be.

Abstract

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Endothelial Cells / metabolism
Fatty Acid-Binding Proteins
Fatty Acids
Ferroptosis*
Humans
Neoplasm Recurrence, Local
Stearoyl-CoA Desaturase / metabolism
Tumor Microenvironment

Substances

FABP4 protein, human
Fatty Acid-Binding Proteins
Fatty Acids
SCD1 protein, human
Stearoyl-CoA Desaturase