Human cerebrospinal fluid affects chemoradiotherapy sensitivities in tumor cells from patients with glioblastoma

Author:

Stringer Brett W.12ORCID,De Silva Manam Inushi12ORCID,Greenberg Zarina1ORCID,Noreña Puerta Alejandra12ORCID,Adams Robert12ORCID,Milky Bridget12ORCID,Zabolocki Michael12,van den Hurk Mark1ORCID,Ebert Lisa M.345ORCID,Fairly Bishop Christine26ORCID,Conn Simon J.2ORCID,Kichenadasse Ganessan26ORCID,Michael Michael Z.26ORCID,Ormsby Rebecca J.2ORCID,Poonoose Santosh2ORCID,Bardy Cedric12ORCID

Affiliation:

1. South Australian Health and Medical Research Institute (SAHMRI), Laboratory for Human Neurophysiology and Genetics, Adelaide, SA, Australia.

2. Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.

3. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.

4. Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.

5. Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.

6. Flinders Medical Centre, SA Health, Adelaide, SA, Australia.

Abstract

Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed 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) tumors from 25 patients. We found that CSF induces tumor 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 the survival of patients with GBM.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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