The general aim of the thesis project is to better understand the pathophysiology of Noonan syndrome (NS), a relatively frequent (1/2000 live births) genetic disorder associating cranio-facial features, cardiopathies, short stature and learning disability. Beside these congenital involvements, patients with NS also display a wide range of clinical traits that are reminiscent of early ageing, the pathophysiology of which is misunderstood: bone defects (e.g. decreased bone mass), muscle weakness, predisposition to myeloproliferative disorders (e.g. juvenile myelomonocytic leukaemia, JMML) and metabolic imbalance (e.g. insulin resistance). Interestingly, we and other obtained striking evidences that many of NS impairments are related to the dysfunction of cells from the myelomonocytic lineage : myeloid precursors in JMML, osteoclast in bone defects, monocytes/macrophages in insulin resistance. As a result, our project now aims

1. to understand the cellular and molecular mechanisms that confer on these cells their pathophysiological potential with a particular focus on the pro-senescent potential of RAS/MAPK hyperactivation,
2. to assess the relative contribution of myelomonocytic cells to the development of the different traits of the disease, and
3. to translate the obtained observations to the clinics.

Cutaneous melanoma is a very aggressive and immunogenic skin cancer that can be treated by immunotherapy based on the administration of antibodies neutralizing CTLA-4 and PD-1, two immune checkpoints expressed on the surface of activated T lymphocytes, acting as a real brake on lymphocyte activation. To date, the best clinical responses in patients with advanced melanoma have been obtained with the combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). However, almost half of patients with metastatic melanoma do not respond to this treatment and there are no biomarkers predictive of resistance. In this context, cellular senescence, a process of genetic, epigenetic and metabolic reprogramming as well as morphological modifications of the cell during aging, seems to play a dual role in resistance to immunotherapy.

The thrombotic risk, mainly due to blood platelet dysfunctions, has a considerable impact in the cardiovascular complications in elderly. However, the mechanisms involved in the increased thrombotic risk and platelet dysfunctions associated to aging are still poorly characterized and therapeutic strategies are very limited. In this context, it seems urgent (i) to better understand the mechanisms involved in the dysfunction of platelet production and activation in an aging context and (ii) to find new pharmacological platelet targets or biomarkers in order to prevent and limit thrombotic complications. The research PhD project aims to finely study the processes of production and activation of blood platelets, from molecular mechanisms to pathophysiology, in an aging context. This project will use transgenic mouse models and a panel of in vivo experimental procedures in mice as well as in vitro and ex vivo imaging and biochemical techniques.

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.

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.