Ph. D. Project
Anti-tumour impact of GPER membrane estrogen receptor expression and functionality on glioblastoma
2023/09/07 - 2026/09/06
Gliomas are the most common primary tumors of the central nervous system in adults. The most severe form is glioblastoma (GBM) with an estimated incidence of 6/100,000. Despite progress, recurrence is systematic and median survival is less than 15 months. Numerous sources indicate that non-menopausal women have a 2-fold lower risk of developing glioma than men and that estrogen intake increases survival. While the link between gender and the incidence of brain tumors is undoubtedly established, no data are currently available on the role of estrogen response pathways, which are dependent on the GPER membrane receptor. However, several preclinical studies carried out on rodents confirm this protective role of estrogens or of 2-methoxyestradiol, a natural metabolite of 17β-estradiol produced locally in the brain and a ligand of GPER.
This request for thesis funding is a continuation of work initiated in 2020 in CRAN laboratory on the impact of steroid hormones on growth and response to anti-cancer treatment in GBM. More precisely, the first results were obtained within the BioSiS department in the framework of Alex Hirtz's thesis (defense 13/12/2022) in close collaboration with the neuro-oncology department of the CHRU of Nancy, and financed by the Cancéropôle Grand-Est and the CNRS INS2I (Emergence 2020) We have thus shown that GBMs could be categorized as estrogen-sensitive tumors (Hirtz, 2020; hal-03045654). In a multidisciplinary study of more than 500 GBM patients, we identified, among the genes differentially expressed between men and women, the one encoding GPER. Its high expression correlates with better patient survival (Hirtz et al. Cells, 2021; hal-03472082; Hirtz et al. Cancers, 2022; hal-03788895), especially in women with higher circulating estrogen levels. This suggests that not only the expression level but also the functionality of GPER-dependent estrogenic pathways may contribute to better patient survival.

In this context, the main objective of the thesis will be to characterize and model, in vitro and in vivo, the impact of the expression level but also of the GPER-dependent signaling on the growth and the infiltrative character of GBMs according to the physiological hormonal environment. With a long-term translational objective, we hope, through a multidisciplinary approach conducted with the IECL, to identify and explain the key mechanisms underlying the anti-cancer effects of GPER modulation, and thus propose a new therapeutic method for GBM.

While some laboratories, notably Sareddy's in the USA, are interested in the role of the estrogen receptor ERβ, our team is for the moment the only one to explore the impact of GPER-dependent signaling in human GBM. This work, in collaboration with the CHRU of Nancy and the IECL, is in line with the objectives of the BioSiS department, in which the study of GBM is a strong axis. It also meets the objectives of axes 3 and 4 of the INCa 2021-2030 ten-year cancer control strategy and the 2030 Digital Health Innovation Plan.

In vitro, we will characterize the expression level of GPER according to its localization in the tumor mass and identify its molecular signature by comparing the transcriptome of GBM cells expressing GPER at different levels and exposed or not to G-1, the specific agonist of this receptor. The PhD student will collect multimodal molecular and cellular data from 2D/3D cell cultures and from patient samples collected at the Nancy University Hospital. In collaboration with mathematical colleagues from the IECL, we aim at a triple objective by modeling experimental data obtained or available in public patient databases: (i) to develop survival analysis techniques based on the analysis of multimodal data (transcriptomes/images), (ii) to complete our analysis by understanding the key mechanisms underlying the anti-cancer effects of GPER modulation. In particular, we will focus on describing the causal graph linking the different explanatory variables involved in patient survival; (iii) to complete this causal graph by proposing a method for inferring the effects of modulators of GPER activity on patient survival. All these data will allow to decipher, at different scales, the mechanisms involved in the protective role of GPER towards gliomagenesis. This part of the project is supported by a grant from the Ligue Contre le Cancer (2023).

From a fundamental point of view, this innovative project will contribute to understand the processes responsible for the differences in GBM incidence and survival between men and women.
Glioblastoma; GPER; estrogen; graph analysis; patients; databases, cell lines.
Biology, Signals and Systems in Cancer and Neuroscience