JEAN-EMMANUEL SARRY ET FANNY GRANAT
ROLE OF METABOLIC DIALOGUE AND SYSTEMIC METABOLISM IN MITOCHONDRIAL ADAPTATION AND THERAPEUTIC
RESISTANCE OF LAM CELLS.
Our work has shown that therapy resistance is due to an increased ability of relapse-initiating leukemic cells (RICs) to induce mitochondrial adaptation and metabolic flexibility in AML. However, while the metabolic characteristics specific to RICs are well established, the metabolic determinants leading to drug resistance remain largely unknown at the level of the different RIC reservoir tissue ecosystems and the whole organism. Numerous intrinsic and extrinsic factors may regulate the mitochondrial adaptive capacities of leukemic cells in response to treatment-induced stress.
In short, our goal is to understand why therapies fail:
- By dissecting the dynamic processes that initiate and sustain the metabolic flexibility and heterogeneity of cell subpopulations that drive relapse ;
- Following the metabolic dialogue of residual cell populations with their microenvironments at the tissue and whole organism levels;
- And by deciphering the role of niche inflammation and diets on the mitochondrial adaptation of resistant cell populations.
Here we propose a novel and integrative view not only to more comprehensively study RIC metabolism, but also to examine the specific metabolic dialogue and cooperation between cancer and stromal cell populations in several distinct ecosystems, and to assess the role of host metabolism in the selection of drug-resistant cells for relapse. Our long-term goal is to apply our findings and knowledge to better stratify with personalized cytogenetic and metabolic biomarkers and to treat cancer patients to delay/prevent/treat their relapse.