PhD

PhD thesis eligible for funding

Title: Role of calcium in glioblastoma aggressiveness: impact of the microenvironment

Summary

Glioblastomas are the most frequent and deadly primary brain tumors in adults. One of the reasons for this poor prognosis may be linked to the presence of a small subpopulation of cells in the tumor, named glioblastoma stem cells. These cells initiate the tumor and generate all the cells in the tumor. They are also resistant to treatment and, because of their stem cell properties, cause the tumor relapse, leading to the patient's death. Previous work by the team has demonstrated the involvement of calcium channels in the function of glioblastoma stem cells. The aim of this thesis is to gain a better understanding of the role of calcium inputs in glioblastoma stem cells, taking into account the effects of the tumor microenvironment and anti-cancer treatments.

Context

Glioblastomas are the most common primary brain tumors in adults. Although glioblastomas are rare, their prognosis remains dismal, with a median patient survival of 15 to 18 months after diagnosis despite treatment. There is therefore an urgent need to increase our knowledge in order to improve the treatment of this devastating cancer. One of the reasons for therapeutic failure is thought to be the heterogeneity of the tumor, and the presence within it of a small subpopulation of cells known as glioblastoma stem cells. These cells are capable of initiating the tumor and generating all tumor cells. They are also resistant to radiotherapy and chemotherapy, and have the capacity to infiltrate nerve tissue. These properties enable them to resist treatment and regenerate all the cells of the tumor mass, causing relapse and death in over 90% of patients.

Description

Over the past two decades, ion channels have emerged as regulators of cancer cells. Previous work by the team has shown that glioblastoma stem cells express non-voltage-dependent store-operated channels (SOCs), and that blocking calcium influx via SOCs decreases the glioblastoma stem cell population. In order to better characterize the role of calcium signaling in glioblastoma, the aims of this thesis are to

- Complete the characterization of the calcium signature of glioblastoma stem cells and the signaling pathways involved

- decipher the relationship between tumor microenvironment, calcium signaling and glioblastoma stem cell properties (migration/invasion, stemness, proliferation)

- Analyze the involvement of calcium channels in resistance to anti-cancer treatments

Methods

Research will be carried out on patient-derived glioblastoma stem cell cultures. The expression of calcium channels will be studied by RT-PCR and Western blot, and their functionality by calcium imaging probes (Fura2, optogenetics). The properties of cancer stem cells will be examined by studying migration, proliferation and self-renewal, notably using techniques previously employed by the laboratory (Terrié et al Cancer. 2021 (14):3428. doi: 10.3390/cancers13143428.).

To study the influence of the microenvironment, two types of strategy will be developed: firstly, injection of cancer cells into brain sections ex vivo, and secondly, the use of conditioned media to collect elements secreted by the microenvironment.

Profile of the applicant

The candidate should have a Master's degree in physiology and/or cancer biology and/or cell biology and/or neuroscience. He/she should have a good knowledge of ion channels and, if possible, of cancer.

The candidate is motivated, proactive, autonomous, rigorous, curious and likes to take initiative. Training in animal experimentation would be a plus. A good level of English (reading, writing and speaking) and good writing skills (English) will be real assets.

Contact:

valerie.coronas@univ-poitiers.fr, nadine.deliot@univ-poitiers.fr

Applications must include:

- A cover letter and CV detailing the applicant's academic background and professional experience (in particular internships completed as part of the applicant's studies).

- Master's course grades (1 & 2) and class rank.

- Contact details for at least two referees (in particular internship tutors).