Thesis – Kasandra AGUILAR CÁZAREZ

Patient-derived models of IDH1-mutant diffuse gliomas: from long-term culture to neuron-tumor interactions

Jury

• Thierry VIROLLE, Research Director, Institut de Biologie Valrose, Nice – Reviewer
• Emmanuelle HUILLARD, Research Scientist, Institut du Cerveau, Paris – Reviewer
• David CASTEL, Research Scientist, Institut Gustave Roussy, Paris – Examinator
• Erika COSSET, Research Scientist, Centre de Recherche en Cancérologie, Lyon – Examinator
• Tristan BOUSCHET, Research Scientist, IGF, University of Montpellier – Guest
• Jean-Philippe HUGNOT, Professor, IGF, University of Montpellier – Thesis supervisor
• Hugues DUFFAU, Professor-Hospital Physician, IGF, University of Montpellier – Thesis co-supervisor

Summary

Adult IDH-mutant diffuse gliomas are infiltrative brain tumors whose interactions with the neuronal microenvironment remain poorly understood. Their study is further limited by the lack of patient-derived models suitable for long-term in vitro models. This thesis aimed to develop complementary human models of IDH-mutant gliomas and investigate their interactions with neurons. First, a non-enzymatic explant culture method was established to generate primary glioma cultures while preserving key tumor characteristics; to overcome their limited proliferative capacity, an immortalization strategy combining hTERT expression and CDKN2A/B disruption was developed. Neuron–glioma interactions were then studied using human induced neurons in two-dimensional co-cultures, revealing increased glioma cell proliferation and phenotypic remodeling, accompanied by transcriptional and proteomic changes. Together, this work provides complementary patient-derived models and highlights the influence of the neuronal microenvironment on IDH-mutant glioma proliferation, plasticity and progression.