Final Report Summary - GLIOMA (Molecular Mechanisms of Glioma Genesis and Progression)
Our ERC project aims to study the molecular mechanisms involved in glioma, the most common tumour of the brain. Based on histopathological characteristics, glioma can be subdivided into 4 grades (I, II, III, IV). Grade IV glioma, also called glioblastoma, is one of the most aggressive tumours with virtually no effective treatment. The study of the molecular mechanisms involved in glioma will facilitate the development of successful therapeutic strategies. Recently, a subpopulation of tumour cells with stem-cell-like properties has been identified in gliomas, as well as in many other tumours. This population of cells, called cancer stem cells, glioma stem cells, brain tumour initiating cells or glioma initiating cells (GICs), is considered to be responsible for the initiation and propagation of glioma, and they are supposed to be the culprits of tumour radio- and chemo-resistance and recurrence of glioma. Still, little is understood regarding the molecular characteristics and regulatory mechanisms that control GIC biology.
Nowadays, most of the models to study cancer are based, on one side in established cell lines that have been in culture for a long period of time or, on the other side, in genetically-modified mouse models. Unfortunately, cells grown in artificial conditions tend to diverge from the characteristics of the real tumour and tumours generated in genetically modified animals do not reproduce the characteristics and cellular heterogeneity found in human tumours. Since we are based within a Hospital, we decided to study cancer as close as possible to the real tumour and study the tumours obtained from patients that underwent surgery in the Hospital. The ERC grant has allowed us to establish an experimental model in collaboration with a multidisciplinary group of neurosurgeons, medical oncologists, and neuropathologists. We obtain tumour samples 15 minutes after surgery and we have set up primary cultures and isolate cell populations from the tumour such as the GIC pool. GICs are orthotopically inoculated in the brain of mice to generate tumours that recapitulate the characteristics of the original human tumour. This provides an optimal in vivo model highly relevant for preclinical studies.
Our work has allowed a better understanding of the oncogenic role of the TGF-beta, Notch and PI3K pathways in glioma and has identified new therapeutic targets against glioma. Moreover, our results have allowed the improvement of the design of the clinical trials using inhibitors of the mentioned pathways providing markers to stratify the patients to be enrolled in the trial.
In addition, we have identified markers to identify GICs, and discerned the molecular mechanisms involved in the self-renewal and differentiation of GICs. Importantly, we have observed that inhibitors of the TGF-beta pathway target GICs preventing tumour recurrence and resistance to conventional therapies.
Nowadays, most of the models to study cancer are based, on one side in established cell lines that have been in culture for a long period of time or, on the other side, in genetically-modified mouse models. Unfortunately, cells grown in artificial conditions tend to diverge from the characteristics of the real tumour and tumours generated in genetically modified animals do not reproduce the characteristics and cellular heterogeneity found in human tumours. Since we are based within a Hospital, we decided to study cancer as close as possible to the real tumour and study the tumours obtained from patients that underwent surgery in the Hospital. The ERC grant has allowed us to establish an experimental model in collaboration with a multidisciplinary group of neurosurgeons, medical oncologists, and neuropathologists. We obtain tumour samples 15 minutes after surgery and we have set up primary cultures and isolate cell populations from the tumour such as the GIC pool. GICs are orthotopically inoculated in the brain of mice to generate tumours that recapitulate the characteristics of the original human tumour. This provides an optimal in vivo model highly relevant for preclinical studies.
Our work has allowed a better understanding of the oncogenic role of the TGF-beta, Notch and PI3K pathways in glioma and has identified new therapeutic targets against glioma. Moreover, our results have allowed the improvement of the design of the clinical trials using inhibitors of the mentioned pathways providing markers to stratify the patients to be enrolled in the trial.
In addition, we have identified markers to identify GICs, and discerned the molecular mechanisms involved in the self-renewal and differentiation of GICs. Importantly, we have observed that inhibitors of the TGF-beta pathway target GICs preventing tumour recurrence and resistance to conventional therapies.