Human cerebrospinal fluid impacts chemo-radiotherapy sensitivities in tumour cells from glioblastoma patients

Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment comprised of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here we examined the effect of human CSF on glioblastoma (GBM) tumours from 25 patients. We found that CSF induces tumour cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear-protein-1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve GBM patient survival. Overall design: Whole transcriptome, single-cell mRNA seq profiles of 10 GBM patient-derived cell lines cultured in glioma medium (termed GM or TME) or CSF generated using 10X genomics.