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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor prognoses.
• Key genetic events in MPNST development include neurofibromin 1 (NF1) disruption, followed by loss of CDKN2A or P53.
• These tumors are often chemo-resistant, necessitating novel therapeutic strategies.

Purpose of the Study:

• To identify distinct transcriptomic and metabolomic features of MPNSTs with CDKN2A loss versus P53 loss.
• To uncover targetable vulnerabilities in MPNSTs, particularly those with NF1 and CDKN2A alterations.
• To investigate the role of the pentose phosphate pathway (PPP) and associated factors in MPNST pathogenesis.

Main Methods:

• CRISPR-Cas9 somatic tumorigenesis in mice for MPNST modeling.
• Multiomic analyses (transcriptomics and metabolomics) to compare CDKN2A-deleted and P53-deleted MPNSTs.
• In vivo and in vitro experiments involving genetic manipulation of key metabolic enzymes and transcription factors (G6PD, NRF2).

Main Results:

• CDKN2A-deleted MPNSTs exhibit a strong dependency on the pentose phosphate pathway (PPP) and NADPH metabolism.
• Disrupting glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, inhibits CDKN2A-deleted MPNST growth and enhances chemosensitivity.
• Knockdown of NRF2, a redox-regulated transcription factor, reduces MPNST growth and G6PD expression, with NRF2 signatures correlating with tumor transformation and patient survival in MPNSTs and PanCancer TCGA data.

Conclusions:

• NRF2-driven PPP dependency represents a targetable vulnerability in MPNSTs, especially in the common NF1/CDKN2A-deleted subtype.
• Targeting G6PD or NRF2 could offer a novel therapeutic approach for these challenging malignancies.
• Understanding the metabolic alterations in MPNSTs provides a basis for developing more effective treatments.