Nanoscale mechanotransduction as a tool for the differentiation of glioblastoma-derived stem cells in a 2D and 3D model

Abstract

Glioblastoma multiforme (GBM) is one of the most common and devastating primary brain tumours. The median survival rate for this tumour is around 15 months, using the gold standard of treatment: maximal surgical resection of the tumour, followed by concomitant chemotherapy and radiotherapy. However, GBM will often return even after these treatments, and this is the case with many other types of cancer. This is believed to be due in part to the existence of cancer stem cells (CSCs) which are unaffected by chemotherapeutic agents. These stem cells can be the source of another tumour which grows after the treatment. Therefore, the question arises: how can we remove the cancer stem cells? One method could be to encourage the stem cells to differentiate, thereby reducing the likelihood of a tumour growing back.

Differentiation describes the process by which stem cells become more specialised, since stem cells maintain their capacity for self-renewal, which is lost upon differentiation into normal cancer cells. There are many signals which a cell receives from its environment, and research has shown that cells can and do respond to changes in their environment. Whether chemical or physical messages are received, the cell may respond in a variety of ways- such as migration, differentiation, hormone secretion, protein production etc. and this includes changes in the extracellular matrix (ECM) to which the cells are connected.

The aim of this project is to establish whether nanoscale mechanotransduction may be a useful tool for the differentiation of stem cells derived from GBM. This approach was used first on stem cells cultured on a flat surface i.e. 2D cell culture, and then a variety of hydrogels were examined to establish a potential model for 3D culture. This culture of GBM stem cells in neurospheres and hydrogels was used as a 3D model to imitate a more realistic environment for the stem cells within the brain.

The 2D-cultured cells or 3D-cultured neurospheres were exposed to a variety of experimental conditions, each with or without the administration of vibrations from a bioreactor, and the response of the cells to these conditions was monitored. These tests required multiple optimisation steps, and highlighted the variety of reactions cells can have in response to changes in their environments. While it is difficult to establish to what extent cells respond to this treatment, the findings of this project hint at the potential in this approach.