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Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide, with patients presenting an overall 5-year survival lower than 15%. NSCLC is characterized by a multitude of tumor-promoting genetic alterations, such as mutations in KRAS, EGFR and TP53 genes. The high heterogeneity and plasticity of lung cancers is one of the main reasons for the failure of current treatment strategies. Importantly, genomic amplification of RICTOR frequently occurs in lung cancer. RICTOR is the defining component of mTOR complex 2 (mTORC2). Moreover, RICTOR-dependent activation of mTORC2 is essential to support lung cancer cell survival and tumor growth in vivo. Despite high therapeutic potential, directly targeting mTORC2 activity in patients remains challenging. Therefore, targeting mTORC2-dependent liabilities may represent a better option for the development of anticancer treatments. Preliminary work from our lab and results from the literature have positioned mTORC2 signaling at the crossroad between translation and metabolism. Hence, deciphering the mechanisms linking mTORC2-dependent translation to the acquisition of specific metabolic liabilities will highlight new therapeutic strategies for the treatment of lung cancer. In this study, I focused on understanding the molecular mechanisms that sustain the rewiring of cancer cell metabolism in the clinically relevant context of RICTOR-overexpressing (RICTOR OE) lung cancer. Using several models, I first evidenced an active role for RICTOR/mTORC2 in the regulation of cancer associated mRNA translation. Preliminary data from the lab indicated that RICTOR silencing in human lung cancer cells was associated with a negative enrichment of hypoxia signatures. Therefore, I first assessed the expression of the different hypoxia-inducible factors (HIF-1α, HIF-2α and HIF-1β) in RICTOR-depleted lung cancer cells. Strikingly, I found that expression of the transcription factor HIF-1β was significantly and consistently decreased upon RICTOR silencing. Importantly, RICTOR-dependent modulation of HIF-1β expression occurred at protein level and was observed in multiple cancer cell lines, highlighting HIF-1β as a potential RICTOR-dependent translational target in lung cancer. Using pharmacological and genetic inhibition of mTOR signaling (RICTOR, RAPTOR and SIN1 siRNAs; mTOR, AKT and PKC inhibitors) I further showed that RICTOR controlled HIF-1β expression through an mTOR-PKC signaling axis, independently of AKT activity. Finally, I demonstrated that HIF-1β levels correlated with mTORC2 activation in vivo, in a mouse model of RICTOR OE. Taken together, my results highlight HIF-1β as a clinically relevant target and support targeting of hypoxia-mediated metabolism as a potential therapeutic approach for the treatment of lung cancer.

lung cancer --- mRNA translation --- metabolism --- mTORC2 --- RICTOR --- HIF1beta --- HIF-1β --- signaling pathways --- Sciences du vivant > Biochimie, biophysique & biologie moléculaire

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Stem cells have for all time, and in the general consciousness, held out the promise of cell 
regeneration, treatment of genetic diseases, grafts of new functional tissues, etc. A global 
solution to very diverse pathologies, as the potential of these cells seems unlimited. 
Today, these very special cells have indeed allowed significant advances in clinical and 
translational medicine, on a small scale. It is therefore fundamental research that has finally 
been able to take advantage of the almost unlimited differentiation potential of these cells, 
making it possible to characterize pathological or cellular processes that were previously 
unanswered, while waiting for a new model.
In this context, this thesis will focus on the reprogramming of somatic blood cells from patients 
into induced pluripotent stem cells (hiPSC) and their differentiation into cardiac contractile 
cells. 
The objectives are multiple: The development and optimization of a protocol for the 
reprogramming of blood cells into pluripotent cells and their subsequent differentiation into 
cardiomyocytes. The characterization of cells at key stages of their development: from stem 
cells to cardiomyocytes. And finally, in the short term, the electrophysiological analysis of the 
induced cardiomyocytes to characterize the impact of specific inherited genetic mutations 
carried by patients with a ventricular arrhythmia phenotype.

cellules souches / cardiomyocytes / hiPSC/ Maastricht University / Uliege/ culture cellulaire --- Sciences de la santé humaine > Médecine de laboratoire & technologie médicale