Des cellules souches neurales (CSN) persistent dans le cerveau de mammifères adultes, y compris l'Homme. Les CSN participent à l'homéostasie tissulaire en générant de nouveaux neurones, permettant le remplacement de certains neurones morts. Cependant, la production de nouvelles cellules se fait en excès et plus de la moitié des cellules nouvellement générées meurent. Les cellules mortes ainsi que leurs débris doivent être éliminés par phagocytose. Dans une première partie de ma thèse, nous avons montré pour la première fois, que les CSN sont capables de phagocytose et que cette activité des CSN est régulée par la protéine S (ProS), une protéine vitamine-K dépendante, et son récepteur MerTK. Une rupture de l'homéostasie tissulaire conduit à des pathologies dont les cancers. Les interactions entre les CSN et des tumeurs cérébrales, les gliomes, sont duelles et étroites : des CSN dont la prolifération est dérégulée seraient à l'origine des tumeurs, mais, à l'inverse, les CSN saines peuvent migrer vers les gliomes et inhiber leur croissance. Dans une deuxième partie de ma thèse, nous avons confirmé l'effet anti-tumoral des CSN et nous avons établi que la ProS sécrétée par les gliomes attire les CSN vers la tumeur d'une part, et d'autre part, que les CSN diminuent la croissance tumorale par la sécrétion de leur ProS. Nous démontrons de plus, que ce processus s'accompagne d'une mort cellulaire des gliomes dont les débris sont phagocytés par les CSN. Mon travail de thèse a permis d'identifier de nouveaux mécanismes impliqués dans le maintien de l'homéostasie tissulaire par les CSN en conditions physiopathologiques. / Neural stem cells (NSC) persist in the brain of adult mammals, including humans. NSC contribute to tissue homeostasis maintenance through the genesis of new neurons that replace part of the cells that are maybe lost. However, the production of new cells is in excess and half of the newly generated cells die. Dead cells and their debris must be removed by phagocytosis. NSC express protein S (ProS) and its receptors, which are involved in phagocytosis. During the first part of my PhD thesis, we established for the first time, using in vitro and in vivo experiments, that NSC possess a phagocytic activity which is regulated by protein S (ProS), a vitamin K-dependent protein, and its receptor MerTK. Tissue homeostasis disruption leads to diseases such as cancers. Interactions between the NSC and brain tumors such as gliomas are dual and complex: glioma may arise from transformed NSC, but, conversely, normal NSC migrate towards glioma and inhibit their growth. Our study confirms the anti-tumoral effect of NSC and demonstrates, for the first time that ProS secreted by gliomas acts on Tyro-3 to attract NSC and that NSC secrete ProS which reduces tumor growth of ProS. In addition, we show that this process results in the death of glioma cells that are then phagocytosed by NSC. Our highlights identified novel mechanisms by which NSC contribute to tissue homeostasis in pathophysiological conditions.

Non-small cell lung cancers (NSCLC) constitute 80-85% of lung cancers and are the leading cause of cancer-related deaths globally. The most common cause is prolonged smoking. Current treatment options for NSCLC include surgery, radiation, chemotherapy, targeted drug therapy, and immunotherapy. Although these medications are effective in the short term, patients often face issues of drug resistance and debilitating side effects with prolonged use. Currently, the use of Zika virus (ZIKV) is being researched as a possible alternative treatment for cancer, which minimizes side effects and the risk of drug resistance. TIM/TAM proteins are identified as the putative ZIKV receptors on the surface of human cells that mediate viral entry through apoptotic mimicry. Once engulfed, the virus can hijack the host cell’s machinery to replicate and propagate the infection. Previous research has shown the potential of using Zika virus as an oncolytic agent in glioblastoma and neuroblastoma cell lines. The success of Zika-induced oncolysis in these cancers opens doors for expanding into other cancers, including NSCLC. Infection of six diverse NSCLC cell lines with ZIKV revealed that three cell lines were sensitive to ZIKV-induced oncolysis while the remaining were resistant. Transcriptome data analysis of TIM/TAM and CD24 mRNA expression levels were compared between ZIKV-sensitive and resistant cell lines, revealing AXL and TIM-1 as potential players in increasing or decreasing ZIKV infection. High AXL (TAM) expression correlated with increased sensitivity to ZIKV, while high TIM-1 (TIM) expression correlated with increased resistance. Experiments with AXL silencing in ZIKV-sensitive cell lines provided evidence of the role of AXL in increasing ZIKV sensitivity. Although further studies with TIM-1 must be done to determine its role in conferring resistance, AXL and TIM-1 have the potential to be biomarkers in predicting tumor sensitivity to ZIKV-induced oncolytic therapy.