MEMECA

Role of membrane lipid-gated mechanosensitive ion channels in cancer biology

Internal reference number: 24/29-143
Start date: September 1st, 2024
End date: August 31, 2029

Partners

PI (spokesperson) Pr Donatienne Tyteca, Université catholique de Louvain (UCLouvain), de Duve Institute (DDUV)

Co-I 1 Pr Philippe Gailly, Université catholique de Louvain (UCLouvain), Institute of Neurosciences (IoNS)

Co-I 2 Pr Joseph Lorent, Université catholique de Louvain (UCLouvain), Louvain Drug Research Institute (LDRI)

Aims of the Coordinated Research Project

Glioblastoma multiforme (GBM) is the most aggressive and most frequent brain tumour in adults and is associated with a very poor survival of 12-18 months. Because of the devastating outcome of the disease, new therapeutic approaches are urgently needed. Reaching this objective requires a better understanding of the mechanisms behind GBM development and progression. In tumours, mechanical properties of the cell surface are generally altered, possibly influencing mechanosensation and leading to exaggerated proliferation, extracellular matrix (ECM) remodeling and increased invasiveness of tumour cells. In addition, GBM growth induces increased intracranial pressure to which tumours are later submitted.

However, it is barely known how mechanosensation in GBM is altered to ensure continuous growth. The global objective of our project is therefore address if and how transmembrane mechanosensitive (MS) channels are deregulated in GBM and how membrane lipid composition and biophysical properties as well as the ECM are involved in the process.

To reach this objective, we will develop various research models of increasing complexity, from model membranes and 2D cell lines to hydrogel platforms of tunable stiffness, 3D organoids and xenograft mouse models using patient-derived GBM cells.

Our project has four specific aims:

1. Determine if 4 pre-selected MS ion channels, i.e. Piezo1, TRPC1, TRPV4 and TRPM7, are involved in GBM in an aggressiveness-based manner. The most promising MS channel(s) defined at this stage will be selected for the next parts of the project.

2. Evaluate whether plasma membrane lipid composition, lateral lipid distribution in domains and transverse lipid asymmetry as well as biophysical properties are altered in GBM and if those alterations could in turn impair the cell functionality and mechanosensitivity. Mechanistically, we propose that: (i) lipid domains could modulate the activity or polarized distribution of MS channels; (ii) changes in membrane composition could influence biophysical and mechanical membrane properties that are involved in conformational changes observed upon MS channel activation; and (iii) direct interaction of MS channels with specific lipids could impose certain channel conformations.

3. Address the role of ECM remodeling in GBM mechanosensing. Indeed, while the ECM composition and its mechanical properties appear modified in GBM, it is not clear how both processes are correlated, and/or take place in an aggressiveness-dependent manner. Moreover, the role of the ECM in interplay with mechanosensing and membrane properties in GBM progression remains to be elucidated.

4. Manipulate membrane lipid composition and properties in a translational approach.

The research team

Theses defended in the context of the Coordinated Research Project

Activities organised as part of the Coordinated Research Project

Publications in connection with the Coordinated Research Project

Contact point in UCLouvain

Pr Donatienne Tyteca, Principal Investigator (spokesperson/coordinator), Université catholique de Louvain (UCLouvain), de Duve Institute (DDUV), E-mail