Published May 17, 2023
| Version v1
Journal article
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Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production
Creators
- 1. Northwestern University
- 2. University of Freiburg
- 3. University of Chicago
Description
During therapy, adaptations driven by cellular plasticity are partly responsible for driving the inevitable recurrence of glioblastoma (GBM). To investigate plasticity-induced adaptation during standard-of-care chemotherapy temozolomide (TMZ), we performed in vivo single-cell RNA sequencing in patient-derived xenograft (PDX) tumors of GBM before, during, and after therapy. Comparing single-cell transcriptomic patterns identified distinct cellular populations present during TMZ therapy. Of interest was the increased expression of ribonucleotide reductase regulatory subunit M2 (RRM2), which we found to regulate dGTP and dCTP production vital for DNA damage response during TMZ therapy. Furthermore, multidimensional modeling of spatially resolved transcriptomic and metabolomic analysis in patients' tissues revealed strong correlations between RRM2 and dGTP. This supports our data that RRM2 regulates the demand for specific dNTPs during therapy. In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models. We present a previously unidentified understanding of chemoresistance through critical RRM2-mediated nucleotide production.
Data availability
The results published here are in part based on data generated by the TCGA Research Network (www.cancer.gov/tcga) and were further analyzed through GlioVis. In addition, these results use data generated by the Human Protein Atlas and GBMSeq (Gephart Laboratory, www.gbmseq.org). Figures, in part, were generated using BioRender (www.biorender.com). All relevant sequencing files were deposited into the GEO repository, accession number: GSE227348. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.Files
Ribonucleotide-reductase-regulatory-subunit-M2-drives-glioblastoma-TMZ-resistance.pdf
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Additional details
Identifiers
- DOI
- 10.1126/sciadv.ade7236
- Other
- oai:uchicago.tind.io:9777
Funding
- National Institute of Neurological Disorders and Stroke
- 1R01NS096376
- National Institute of Neurological Disorders and Stroke
- 1R01NS112856
- National Institute of Neurological Disorders and Stroke
- P50CA221747
- National Institute of Neurological Disorders and Stroke
- R01GM135587
- National Institute of Neurological Disorders and Stroke
- R01GM143334
- Else Kröner-Fresenius Foundation
- Germany Ministry of Education and Research
- MEPHISTO project BMBF