Multiomics analysis and modeling to predict metabolic response in the resistance to leukemia therapies

PhD proposal

Supervisor: J.E. SARRY

Team J.E. Sarry – CRCT

Despite a high rate of complete remission after treatment with genotoxic agents, the prognosis is poor in human acute myeloid leukemia (AML). Front-line chemotherapy is highly effective in ablating leukemic cells, but relapses caused by tumor regrowth initiated by resistant leukemic clones (RLCs) are observed in the majority of patients. The biology of therapeutic resistance currently represents an active area of research. However, the molecular mechanisms underlying drug resistance are still poorly understood in AML, especially in the in vivo context. To address this issue and to characterize chemoresistance and minimal residual disease (MRD), we established a robust patient-derived xenograft (PDX)-based preclinical model that predicts response to chemothepeutics in AML patients. Taking advantage of these in vivo models, we demonstrated that in vivo drug tolerant/resistant AML cells present an enhanced mitochondrial oxidative metabolism. Furthermore, our studies shown that the catabolic flexibility, the inflammatory response, and the metabolic cooperation between stromal and leukemic compartments are key players of mitochondrial activities of chemoresistant AML cells13,14. Therefore our previous results provide not only new targets but also a strong scientific rationale for ongoing clinical trials that assessed emerging combinatory therapies with different mitochondrial inhibitors in AML. Altogether, our work suggests that the mitochondrial function, the metabolic cooperation and symbiosis between the stromal and leukemic compartments inside the bone marrow niche, and inflammatory/stress responses, play a crucial role in drug resistance of AML.

 In light of our current results and evidences, our working hypothesis is that the microenvironment-tumor interplay regulates mitochondrial metabolism of AML cells through the activation of key transcriptional factors and regulons, and of stress responses, leading to drug resistance in vivo. To address this hypothesis and to further decipher the heterogeneity of these drug resistance pathways at both single cell and tissue levels, our methodological strategy is based on functional approaches using well-characterized AML cell lines and primary patient samples in vitro and in our xenograft NSG model coupled to bulk and single cell omics and computational approaches. Finally, our preliminary single cell transcriptomic analysis of cells collected from PDX and patients at diagnosis and relapse uncovered a subpopulation endowed with a specific transcriptional profile implicated into (and predictive of) the relapse in AML.

Key Words: AML, drug resistance, metabolism, in silico modeling, computational prediction


Adipose tissue microbiota and ageing

PhD proposal

Supervisor: J. Galitzky

Team A. Bouloumié – I2MC

The development of adipose tissue is dependent on its interaction with the environment and particularly the nutritional one. These last years, the intestinal microbiota has emerged as an important vector in the link between nutrition and fat mass growth. But other components including gender, age and location of the fat depots have also to be considered. Our hypothesis is that there is a molecular relationship between the microbiota which is influenced by age and nutrition and the immune and progenitor cells of the fat depots which govern the structure, diversity and metabolic plasticity of the tissues. We have recently shown that bacteria are present in the tissue and could be essential factors in the interface between the environment and the physiology of the tissue. The research project proposes to study the molecular interaction between bacteria, particularly tissue bacteria, and the microenvironment of fat depots including progenitor cells and immune cells with a particular focus on cell senescence.

Using metagenomic approaches carried out on subcutaneous and visceral adipose depots from human cohorts (FLORINASH cohort), we will analyze the composition and diversity of the tissue microbiota of human adipose depots and the impact of obesity, gender, age and associated pathologies. In parallel, we will dissect the molecular aspects of the interaction between bacterial populations and cells of the adipose microenvironment. We will study the impact of bacteria of interest and their products (identified by our previous work and by the approaches mentioned above) on cell senescence in the microenvironment of fat depots and inversely the impact of cell senescence on bacteria sensing, growth and metabolism. The intracellular pathways will be analyzed with an interest on pathways common to bacterial sensing and senescence including TLRs, NLRs, inflammasome and STING pathways. Finally, the causality of bacterial populations and / or their products of interest in controlling the diversity and metabolic plasticity of fat depots will be studied in vivo in the unique model developed in the team of humanized axenic mice.

Key words: Progenitor cells, senescence, Bacteria, Inflammation, Metabolism, Plasticity