CDKN2A and TP53 loss differentially affect metabolic reprogramming in malignant peripheral nerve sheath tumors
Creators: name: McGivney, Gavin Riley
Publisher: name: University of Iowa
Year: 2026
Subjects: subject: CRISPR
subject: Malignant Peripheral Nerve Sheath Tumors
subject: Metabolomics
subject: Pentose Phosphate Pathway
subject: Sarcoma
subject: Genetics
subject: FOS: Biological sciences
subject: Metabolism

description: Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of soft tissue sarcoma that account for 5-10% of all soft tissue sarcomas. These tumors arise from Schwann cell lineage cells and are often associated with neurofibromatosis type 1 (NF1), a genetic disorder that predisposes patients to tumor development. MPNSTs are challenging to treat, with poor survival rates and high recurrence, even after surgery. Existing therapies, including chemotherapy and radiation, offer limited benefits. Tumor suppressors CDKN2A and TP53 are commonly mutated or lost in patient MPNSTs, however, little is known about their differential effects on MPNST biology. This study focuses on the underappreciated metabolic roles of these key tumor suppressors.
description: In Chapter 2, I directly compare the global roles of CDKN2A and TP53 (Trp53 in mice) in the molecular and metabolic programming of malignant peripheral nerve sheath tumors (MPNSTs). I utilized a CRISPR/Cas9-based somatic tumorigenesis approach to generate MPNSTs in wild-type mice with either Nf1/Cdkn2a or Nf1/Trp53 deletions, allowing for investigation into their distinct effects on tumor biology. Tumor-derived cell lines were analyzed for differences in gene expression and metabolite abundances using RNA sequencing and metabolomic profiling. These studies revealed that Nf1/Cdkn2a-deleted tumors upregulated the pentose phosphate pathway (PPP) and exhibited increased production of NADPH, a key reducing agent utilized for combating accumulation of radical oxygen species (ROS) and oxidative stress. Our findings highlight the differential regulation of key cancer pathways by CDKN2A and TP53 in MPNSTs and suggest that targeting the PPP could be a potential therapeutic strategy, particularly in CDKN2A-deficient tumors.
description: In Chapter 3, building on the finding from Chapter 2, I hypothesized that inhibiting the pentose phosphate pathway (PPP) would have differential effects on Cdkn2a- versus Trp53-deleted MPNSTs. My results showed that Nf1/Cdkn2a-deleted cells were more sensitive to glucose 6-phosphate dehydrogenase (G6PD) inhibition, both pharmacologically and genetically, with greater reductions in viability compared to Nf1/Trp53-deleted cells. Combining G6PD inhibition with the chemotherapy further improved responses in Nf1/Cdkn2a-deleted cells. The transcription factor, NRF2, is a master regulator of cellular stress response and known regulator of the PPP. Mechanistic studies revealed that the NRF2/G6PD axis is essential for the viability of Nf1/Cdkn2a-deleted MPNSTs. Finally, analyses of human MPNST samples validated the upregulation of NRF2 target genes, including PPP enzymes, in malignant versus benign tumors. These findings identify the NRF2/G6PD axis as a metabolic vulnerability in MPNSTs, particularly in CDKN2A-deficient tumors, offering a promising therapeutic target.
description: In Chapter 4, I explore key unresolved questions and potential future directions prompted by this current research. I consider the underlying mechanisms that could be driving this differential dependence on the PPP for viability. Additionally, I discuss the alternative roles of NADPH beyond mitigating the accumulation of ROS that could be an additional variable in this model. Lastly, I acknowledge and describe the need for in vivo testing of PPP inhibition and endorse future testing of alternative clinical inhibitors targeting additional antioxidant pathways.