Session nouvelles /nouveaux recruté(e)s
Newly appointed scientist
Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells responsible for the production of all blood cell types throughout the life of an individual. Despite their location within the adult bone marrow, HSCs are generated during development from specialized endothelial cells called hemogenic endothelial cells in the main embryonic arteries (dorsal aorta, umbilical and vitelline arteries), an evolutionary conserved mechanism within vertebrate species. HSCs arise through a process called endothelial-to-hematopoietic transition, a lineage switch which is tightly regulated in time and space and polarized to the ventral side of the embryonic aorta. In this respect, HSC production is also thought to rely on a specialized
microenvironment localized underneath the aortic floor that would promote the lineage switch and constitute a niche for the first HSCs. Taken together, HSC formation encompasses intrinsic cues i.e., cell autonomous and extrinsic cues that constitute an unresolved paradigm for cell and developmental biology and a challenge for regenerative medicine, as clinical de novo formation of HSCs is an unmet goal.I investigate these intrinsic and extrinsic regulations using complementary in vitro and in vivo approaches in the avian embryo, which is a reliable and accessible vertebrate model, and using human iPSCs.On one hand, I am developing an in vitro system that allows mesodermal cells to differentiate into endothelial cells, then into hemogenic endothelial cells, and finally into hematopoietic cells. This system will be used to detect the discrete cellular differentiation steps leading to HSC formation using single cell RNA sequencing technology. The main goal is to elucidate the initial steps of HSC formation to eventually optimize in vitro culture systems for clinical grade HSC production.On the other hand, I use microsurgical techniques to alter the normal microenvironment of the aorta, the cradle of HSC formation, and evaluate the consequences for HSC development. Combining these ablation experiments with spatial transcriptome approaches will decipher the role of the aortic environment in the formation of the first HSCs.
Amongst the hematological malignancies, T-cell acute lymphoblastic leukemia (T-ALL) constitute a class of highly aggressive cancers in children, adolescent, and young adult, marked by aggressive behavior and poor clinical response, notably for relapsing cases. T-ALL relapses remain associated with dramatically dismal prognosis despite salvage chemotherapy. As in numerous cancers, genetic lesions leading to aberrant PI3K signaling are frequent in T-ALL and convey adverse outcomes from limited therapy response to early relapse and dismal survival rates. Therefore, it is urgent to identify those with the highest risk of relapse to be allocated to innovative treatment strategies.
We conduct translational approaches to tackle leukemia resistance, by notably exploring oncogene-associated vulnerabilities, and proposing novel targeted therapies to improve the outcomes of the patients.Metabolic plasticity is a hallmark of cancer cells that permits their adaptation to the microenvironment and favors evading the pressure of chemotherapy. The deregulated activation of Notch1 and PI3K signaling, two major drivers of leukemia progression, sustains a metabolic addiction of cancer cells to glutamine and glucose. We identify a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR mimics glucose limitation and reveals the singular plasticity of PI3K-altered blasts toward the mobilization of glutamine as a salvage pathway to ensure their survival. Subsequently, we showed that the combination of glutamine degradation and mTOR inhibition demonstrates robust anti-leukemic properties in PI3K-driven disease in pre-clinical models in vivo (Fig 1c-d). We also validated this new therapeutic strategy in patients. We report the case of five patients suffering from R/R leukemia with PI3K signaling alteration, with a complex clinical history, treated with the association Erwinase/Torisel (ET). All five patients achieved a rapid response (Fig 1e). After complete remission, three patients received consolidation therapy consisting of allogeneic SCT or donor lymphocyte infusion. Two patients remain alive, while two patients rapidly progressed after the discontinuation of ET treatment. We propose a promising treatment combining an asparagine and glutamine degrader (Erwinase) with a PI3K signaling inhibitor (Torisel) that should be considered as a therapeutic option in a bridge-to-transplant approach for R/R T-ALL/LL with PI3K signaling deregulation. We show that metabolic plasticity conveys a unique and targetable vulnerability in PI3K-driven leukemia with promising results in clinical settings.
Cytokines are key immune regulators, with their interactions with extracellular receptors central to immune responses. However, their pleiotropic behavior, where one cytokine can impact multiple cell types both beneficially and adversely, poses challenges in therapeutic contexts.
Our study found that the efficacy of Interleukin (IL)-2, vital for T cell immunity, is influenced by extracellular pH. Specifically, lactic acid produced by tumors reduces IL-2 signaling in the tumor's acidic environment, inhibiting STAT5 activation and reducing the effectiveness of high-dose IL-2 treatments. Using directed evolution, we created a pH-responsive IL-2 variant, Switch-2, which has improved binding to the IL-2 receptor and displays enhanced activation
in acidic conditions. This leads to significant tumor rejection with reduced side effects. Furthermore, our investigation into IL-10, a cytokine with dual immunoregulatory roles, highlighted challenges in its therapeutic use due to its pleiotropic effects. We hypothesized that weak binding affinity of IL-10 to the IL-10Rβ subunit might be responsible for its limited clinical effectiveness. Employing yeast surface display, we generated an IL-10 variant with a 1000-fold increased affinity for IL-10Rβ. This enhanced variant demonstrated increased receptor heterodimerization, leading to stronger STAT activations, and showed greater gene expression activation in CD8 T cells. Moreover, CAR-T cells exposed to this variant exhibited increased cytolytic activities, suggesting potential for improved IL-10-based cancer treatments.In addition, our development of IL-2/IL-10 duokines, by fusing IL-10 and IL-2, introduces de-novo signaling and presents a promising therapeutic approach. This combination harnesses the tumor-fighting capabilities of IL-2 while leveraging the immune-regulating functions of IL-10, offering optimized immune responses against cancer.