Metabolic Plasticity in Cancer

Metabolic plasticity allows cancer cells and their microenvironment to adapt to physiological stress, variations in nutrients, and anticancer treatments. Our program aims to understand how mitochondrial function and mTORC1 signaling promote tumor progression, immune adaptation, and therapeutic resistance. The goal is to identify metabolic vulnerabilities that can be targeted in cancer therapy.

Our research is organized into three complementary areas.

• Track 1 (Principal Investigator – Svetlana Dokudovskaya): Metabolic adaptation and treatment resistance. We are studying how the dysregulation of the mTORC1 suppressor, GATOR1, disrupts mitochondrial homeostasis and contributes to cisplatin resistance. We have shown that GATOR1 regulates autophagy, mitophagy, and the response to DNA damage, and that its loss reduces the intracellular accumulation of cisplatin while increasing mTORC1 activity.

• Research Area 2 (Principal Investigator – Camille Bleriot): Metabolic interactions in the tumor microenvironment. Using mouse models, spatial transcriptomics, and single-cell approaches, we are studying the differentiation of tumor-associated macrophages in pancreatic cancer. We have identified populations expressing TREM2 and CD36, suggesting that metabolic signals control macrophage specialization and their pro-tumoral functions.

• Research Area 3 (Principal Investigator – Catherine Brenner): Translational targeting of mitochondrial pathways and mTORC1. We have shown that disruption of the mitochondrial AIF/CHCHD4 complex reduces metabolic flexibility and induces apoptosis in tumor cells that overexpress these two proteins. In collaboration with chemists and clinicians, we have identified the flavonoid derivative M30-E05 as a promising anticancer compound for pediatric and adult solid tumors.

Future studies will focus on tumor metabolism associated with obesity, immuno-metabolic interactions, and the development of new therapeutic strategies targeting mitochondrial and mTORC1 pathways.