Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production

Author:

Perrault Ella N.1ORCID,Shireman Jack M.1ORCID,Ali Eunus S.2ORCID,Lin Peiyu1,Preddy Isabelle1,Park Cheol1ORCID,Budhiraja Shreya1,Baisiwala Shivani1,Dixit Karan3ORCID,James C. David14ORCID,Heiland Dieter H5678,Ben-Sahra Issam2ORCID,Pott Sebastian9ORCID,Basu Anindita9ORCID,Miska Jason13ORCID,Ahmed Atique U.13ORCID

Affiliation:

1. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

2. Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

3. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

4. Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

5. Microenvironment and Immunology Research Laboratory, Medical-Center, University of Freiburg, Freiburg, Germany.

6. Department of Neurosurgery, Medical-Center, University of Freiburg, Freiburg, Germany.

7. Faculty of Medicine, University of Freiburg, Freiburg, Germany.

8. German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany.

9. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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