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New plan of action against ovarian cancer

Fatima Mechta-Grigoriou, chef de l'équipe "Stress et cancer" au sein de l'unité 830 Inserm "Génétique et biologie des cancers" à l'Institut Curie.

Fatima Mechta-Grigoriou’s team from Institut Curie just identified a brand new mecanism on ovarian cancer’s treatment. Her work just got published in the prestigious scientific journal Cell Metabolism.

“Our work is challenging the 100-year-old notion that all cancers, including ovarian cancer, are addicted to glucose,” applauds Fatima Mechta-Grigoriou, head of the Stress and Cancer team at Institut Curie (Inserm unit U830, a team certified by the Ligue Nationale Contre le Cancer). These researchers have applied an array of cutting-edge techniques – including proteomics, metabolomics and bioenergetics – to ovarian cancer cells to discover the secrets that they hold; namely the proteins they contain, the chemical reactions that take place and the source of their energy. They have been able to uncover information about high-grade serous cancers, the most formidable of ovarian cancers.

And it turns out that, against all expectations, some of these tumors do not feed on glucose but prefer fatty acids and glutamine (an amino acid made up of proteins). The research team has thus shed light on an innovative molecular mechanism by identifying the very surprising role of a PML (ProMyelocytic Leukemia) protein which is well known in leukemia.  And better still, the scientists have discovered that their original metabolism makes these cancers more vulnerable to certain types of chemotherapy, namely taxanes and platinum derivatives.

Once again, this work was made possible by the contributions of Basic research to knowledge of cancer, aided by the location of the “Stress and cancer” laboratory at Institut Curie Research Center in proximity to the Hospital Group. This enabled access to biological material from the hospital and fostered exchanges on medical observations and scientific hypotheses.

Fatima Mechta-Grigoriou now hopes that “physicians will seize these new discoveries to launch clinical trials”. First up, a molecular diagnosis of these tumors to ascertain their different types, followed by new and more effective treatments against cancer. This is crucial given that we know that ovarian cancer kills more than 3,000 women each year in France.

Reference of the publication

High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOC rely on oxidative phosphorylation, supported by glutamine- and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1a axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1a. Active PGC-1a increases synthesis of electron transport chain complexes thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOC exhibit increased response to conventional chemotherapies, in which increased oxidative stress, PML and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1a-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer.

Sources : Cell Metabolism, September, 20th – PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers