Investigating the role of TMEM16A/ANO1 ion channels in treatment-resistance in glioblastoma

About the Project

Glioblastoma is initially treated by surgery followed by radiotherapy and chemotherapy but tends to recur with poor prognosis. This project will utilise novel patient-derived 2D and 3D glioblastoma cell models and investigate how calcium-activated chloride channels, TMEM16A/ANO1, signal within the cancer stem-cell compartment, driving treatment-resistance and disease recurrence. We will test whether pharmacological modulators of ANO1 channels can prolong treatment-response within laboratory models and elucidate the underlying molecular mechanisms.

Brain tumours are the leading cause of cancer deaths in children and adults under the age of 40. High-grade Glioblastoma is treated by surgery followed by chemotherapy and radiotherapy but recurs in the majority of patients and new treatments need to be developed. Recurrence is driven by cancer stem cells which enable treatment-resistance and it is known that a number of ion channels are involved.

In this project we will test the role of TMEM16A/Ano1 calcium-activated chloride channels in glioblastoma cancer stem cells in driving treatment-resistance both to radiotherapy and chemotherapy. We will characterise physiological expression and function of TMEM16A/Ano1 channels in patient-derived 2D and 3D glioblastoma stem cell models in response to irradiation or chemotherapy, and compare with glioblastoma tumour cells.

We will characterise the effects of modulating ion-channel expression by pharmacological inhibition or knockdown/overexpression and its impact on radiation response focussing on cancer readouts of cell survival, cell migration and cell death. Using co-cultures of glioblastoma cells with tumour-associated macrophages we will also assess how the tumour microenvironment immune ‘tunes’ glioblastoma phenotypical characteristics before and after irradiation in combination chemotherapy.

Candidate pharmacological modulators will also be tested against cellular models of normal brain including neurons, brain-derived endothelial cells and non-malignant glial cells.

The project will identify relevant molecular physiological targets for the development of new approaches to improve time to recurrence for brain tumour patients.