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
Affiliations
Géraldine Luis
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
Adrien Godfroid
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
Shin Nishiumi
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
Jonathan Cimino
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
Silvia Blacher
Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium
Erik Maquoi
Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium
Coline Wery
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
Alice Collignon
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
Rémi Longuespée
Mass Spectrometry Laboratory, MolSys Research Unit, University of Liège, Liège, Belgium; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
Laetitia Montero-Ruiz
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
Isabelle Dassoul
Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium
Naima Maloujahmoum
Metastasis Research Laboratory, GIGA Cancer, University of Liège, 4000, Liège, Belgium
Charles Pottier
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
Gabriel Mazzucchelli
Mass Spectrometry Laboratory, MolSys Research Unit, University of Liège, Liège, Belgium
Edwin Depauw
Mass Spectrometry Laboratory, MolSys Research Unit, University of Liège, Liège, Belgium
Akeila Bellahcène
Metastasis Research Laboratory, GIGA Cancer, University of Liège, 4000, Liège, Belgium
Masaru Yoshida
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
Agnès Noel
Laboratory of Biology of Tumor and Developmental Biology, GIGA Cancer, Liège University, Liège, Belgium
Nor Eddine Sounni
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; Corresponding author. Cancer Metabolism and Tumor Microenvironment Group, Laboratory of Tumor and Developmental Biology, GIGA-cancer, Liège University, Liège, Belgium.
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.
