GIGA 2021 Annual Report 33 Nor Eddine Sounni’s group (LBTD, GIGA-Cancer) has provided new insight on mechanisms driven by lipid transport and desaturation in protecting cancer cells from ferroptosis and promoting tumor recurrence, a serious impediment in cancer treatment. The group has previously reported evidence of tumor lipid addiction during recurrence after treatment and metastatic dissemination. Here, in collaboration with Yoshida’s laboratory from Kobe University in Japan and Bellahcène’s group at the GIGA-Cancer, they applied lipidomics to in vivo tumor models of hypoxia/reoxygenation and revealed a particular enrichment of recurrent tumors in mono-unsaturated fatty acids (MUFA). They demonstrated that lipid desaturation by Steroyl-CoA-Desaturase-1 (SCD1) and lipid transport by fatty-acid-binding-protein-4 (FABP4) contribute to such tumor recurrence. SCD1 and FABP4 were found highly overexpressed in residual tumors from mouse and human cancers. Mechanistically, they revealed a cooperation between cancer cells producing SCD1 upon therapy-derived metabolic stress and tumor endothelial cells releasing FABP4 that increases lipid uptake and lipid droplets in cancer cells. SCD1 switches the balance of MUFA/PUFA (poly-unsaturated fatty acids) in favor of MUFA. PUFA are the main substrates for lipid oxidation that induces ferroptosis, a redox- active iron-induced cell death. Notably, FABP4 and SCD1 inhibition sensitized cancer cells to ferroptosis. Overall, this work reveals that SCD1 and FABP4 constitute vulnerabilities that can be targeted to suppress tumor recurrence.
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