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Place des signalisations autophagique et neurotrophiques dans le Gliobastome Multiforme : implications pour les cellules souches cancéreuses

Abstract : Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain tumor. Despite a treatment combining radiotherapy and chemotherapy, recurrence is almost systematic because of the tumor cell resistance. Indeed, they are able to develop various survival mechanisms, such as autophagy, which is amplified in hypoxic conditions. Furthermore, several growth factors, such as neurotrophins, promote cell survival signaling. These two survival processes are highly related to the development of cancer stem cells (CSCs). CSCs have been identified as contributing to the GBM resistance to radiotherapy and chemotherapy treatments and recurrence by their ability to reconstitute a tumor. Our two main objectives were: i) to identify the role of the autophagy and neurotrophin signaling, mediated by the receptor TrkC, in survival of GBM cells under hypoxic stress condition, ii) to study the involvement of these two mechanisms in the CSCs resistance to treatment processes, and their maintenance within the tumor. Our results (assessed on four GBM cell lines) showed that both autophagy and TrkC signaling were activated in hypoxic stress conditions (<24h). Interestingly, there is a compensation between these two survival pathways. We demonstrated that the loss of one of the pathways modifies the phenotype of the CSC population, whether at a functional level (proliferation, resistance to Temozolomide) or for the expression of stem cell markers. Thus, the invalidation of these survival pathways could affect the activation state of CSCs, which modifies their resistance to the treatment. This adaptive capacity of CSCs highlights their dynamic aspects in this compartment in the GBM.
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https://tel.archives-ouvertes.fr/tel-02440623
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Submitted on : Tuesday, January 28, 2020 - 2:53:20 PM
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Sophie Hombourger. Place des signalisations autophagique et neurotrophiques dans le Gliobastome Multiforme : implications pour les cellules souches cancéreuses. Médecine humaine et pathologie. Université de Limoges, 2017. Français. ⟨NNT : 2017LIMO0103⟩. ⟨tel-02440623v2⟩

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