Role of tumor cell metabolic plasticity in resistance to therapy

Relapse in many cancers is driven by a small subpopulation of residual or resistant cancer cells that remain viable following chemotherapy, while the majority of tumor cells are rapidly eliminated. Increasing evidence indicates that these therapy-tolerant cells arise not only through genetic mutations but also through reversible non-genetic mechanisms, involving transcriptomic, epigenetic or translational regulation. However, the metabolic regulation of these mechanisms remains largely unexplored. Such processes enable phenotype switching, allowing a single genotype to adopt multiple functional states in response to environmental cues. Cells in hybrid states, often characterized by partial epithelial-to-mesenchymal transition (EMT), exhibit heightened plasticity and enhanced tolerance to therapeutic stress.

Tumor metabolic heterogeneity is now well documented, with cancer cells displaying diverse nutrient preferences and exploiting distinct metabolic routes. Defining the metabolic programs that sustain therapy-tolerant, plastic cell states therefore represents a critical missing link in our understanding of treatment resistance. My group is investigating these metabolic programs to elucidate how they support phenotypic plasticity and therapeutic resistance.

In High-Grade Serous Ovarian Carcinoma (HGSOC), we previously identified a high-OXPHOS subgroup that initially responds more robustly to platinum/taxane chemotherapy. Nonetheless, nearly all patients ultimately develop resistance, leading to relapse and poor clinical outcomes.

In this seminar, I will address whether platinum-based chemotherapy modulates tumor cell plasticity and promotes the emergence of therapy-tolerant states in ovarian cancer. Our findings suggest that a pre-existing fraction of tumor cells exhibits metabolic flexibility and partial EMT identity, enabling survival under chemotherapeutic pressure. I will discuss our ongoing efforts to characterize this residual state, with a particular focus on metabolic rewiring as a driver of phenotypic plasticity.

Bio: Géraldine Gentric is a permanent research scientist (Chargée de recherche) at Inserm. She obtained her PhD at Institut Cochin under the supervision of Dr. C. Desdouets, where her work focused on metabolic liver disease, oxidative stress and cell cycle. She then spent 12 years at Institut Curie in the laboratory of Dr. F. Mechta-Grigoriou, during which she developed strong expertise in cancer metabolism, intra-tumor heterogeneity, and adaptive responses to therapeutic stress. In September 2025, Géraldine Gentric established her own group, MetaboCare – “Cancer Metabolism & Therapy Resistance”, within the Inserm Unit 981. Her group investigates how metabolic rewiring supports phenotypic plasticity and the emergence of therapy-tolerant cancer cell states, with a particular focus on ovarian cancer.