The association of SLC6A6 with treatment resistance in glioblastoma

Glioblastoma (GBM) is an incurable and aggressive form of brain cancer that predominantly affects adults and is the cause of the majority of primary brain tumour related deaths. The prognosis is poor with median survival time of only 12-15 months following diagnosis despite aggressive standardised treatment of debulking surgery and chemoradiotherapy. Almost 100% of GBM tumours recur. This is likely due to inherently treatment resistant cells within the primary tumour that survive and dominate tumour recurrence. SLC6A6 was deemed a potential for conferring treatment resistance in GBM due to its significantly upregulated expression in recurrent tumours, and previous associations to other cancers. SLC6A6 encodes a taurine transporter, TauT, that has an important role in embryonic brain development and neurogenesis in the adult brain. The role of SLC6A6 in the impact of standard treatment was investigated using shRNA knockdown and TauT inhibitors. This work was performed in vitro using 3D spheroid models imaged using a bespoke imaging and analysis platform that I led the development of. Both established and patient derived cell lines cultured in serum free media were used to represent different aspects of GBM biology. Results showed that TauT inhibitors significantly alter treatment response in different directions in the cell lines. Furthermore the size of the effect implicated an off-target effect: γ-aminobutyric acid (GABA) signalling modulation. RNA sequencing indicated that cells were being transcriptionally reprogrammed in response to standard treatment in different ways, in keeping with a parallel finding from analysis of primary and recurrent patient tissues. The latter suggests that there are two responder subtypes in GBM, with different treatment resistance mechanisms underpinning them. A possible explanation for these results is, then, that the cell lines fall into different categories of GBM responder subtypes. The varying responses seen after GABA modulation indicate that stratifying treatment based on the response subtype would be beneficial.