Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs

Gavin R. McGivney; Qierra R. Brockman; Nicholas Borcherding; Amanda Scherer; Adam J. Rauckhorst; Wade R. Gutierrez; Shane R. Solst; Collin D. Heer; Akshaya Warrier; Warren Floyd; David G. Kirsch; Vickie L. Knepper-Adrian; Emily A. Laverty; Grace A. Roughton; Douglas R. Spitz; Eric B. Taylor; Rebecca D. Dodd

doi:10.1126/sciadv.adu2906

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Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs

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Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs

Gavin R. McGivney, Qierra R. Brockman, Nicholas Borcherding, Amanda Scherer, Adam J. Rauckhorst, Wade R. Gutierrez, Shane R. Solst, Collin D. Heer, Akshaya Warrier, Warren Floyd, …

Science advances, Vol.11(33), eadu2906

08/15/2025

DOI: 10.1126/sciadv.adu2906

PMCID: PMC12346278

PMID: 40802750

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Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor survival rates. Loss of CDKN2A or P53 following NF1 disruption is a key event in MPNST development. Here, we used CRISPR-Cas9 somatic tumorigenesis in mice to identify transcriptomic and metabolomic features distinguishing CDKN2A- versus P53-deleted MPNSTs. Convergent, multiomic analyses revealed that CDKN2A-deleted MPNSTs are especially dependent on the pentose phosphate pathway (PPP) and NADPH metabolism for growth and viability. Disruption of glucose-6-phosphate dehydrogenase (G6PD), the PPP rate-limiting enzyme, slowed CDKN2A-deleted MPNST growth and sensitized MPNSTs to standard-of-care chemotherapy. Knockdown of the redox-regulated transcription factor NRF2 slowed MPNST growth and decreased G6PD transcription. Analysis of patient MPNSTs identified a NRF2 gene signature correlating with tumor transformation. Furthermore, G6PD and NRF2 expression in PanCancer TCGA samples correlates with patient survival. This work identifies NRF2-PPP dependency as a targetable vulnerability in these difficult-to-treat MPNSTs, particularly in the NF1/CDKN2A-deleted majority.

Molecular Biology

Biomedicine and Life Sciences

Cancer

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Title: Subtitle: Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs
Creators: Gavin R. McGivney - University of Iowa
Qierra R. Brockman - University of Iowa
Nicholas Borcherding - Washington University in St. Louis
Amanda Scherer - University of Iowa
Adam J. Rauckhorst - University of Iowa
Wade R. Gutierrez - Mayo Clinic in Arizona
Shane R. Solst - University of Iowa
Collin D. Heer - University of Iowa
Akshaya Warrier - University of Iowa
Warren Floyd - The University of Texas MD Anderson Cancer Center
David G. Kirsch - University Health Network
Vickie L. Knepper-Adrian - University of Iowa
Emily A. Laverty - University of Iowa
Grace A. Roughton - University of Iowa
Douglas R. Spitz - University of Iowa
Eric B. Taylor - University of Iowa
Rebecca D. Dodd - University of Iowa
Resource Type: Journal article
Publication Details: Science advances, Vol.11(33), eadu2906
DOI: 10.1126/sciadv.adu2906
PMID: 40802750
PMCID: PMC12346278
NLM abbreviation: Sci Adv
ISSN: 2375-2548
eISSN: 2375-2548
Publisher: American Association for the Advancement of Science
Grant note: ; NF170067 / ; OT2-OD030544 (Metabolomics Workbench) / ; 2020-01-002 / ; DK104998 / ; U2C-DK119886 (Metabolomics Workbench) / ; CA197616 / ; NS119322 / ; CA217797 / ; DK138664 / ;
Alternative title: The pentose phosphate pathway revealed as a metabolic vulnerability in MPNSTs
Language: English
Date published: 08/15/2025
Academic Unit: Dermatology; Molecular Physiology and Biophysics; Microbiology and Immunology; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984946610602771

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