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Dissertation
CDKN2A and TP53 loss differentially affect metabolic reprogramming in malignant peripheral nerve sheath tumors
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007561
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- CDKN2A and TP53 loss differentially affect metabolic reprogramming in malignant peripheral nerve sheath tumors
- Creators
- Gavin Riley McGivney
- Contributors
- Rebecca D Dodd (Advisor)Eric B Taylor (Advisor)Dawn E Quelle (Committee Member)Munir R Tanas (Committee Member)Christopher S Stipp (Committee Member)Brandon S. J. Davies (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cancer Biology)
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007561
- Publisher
- University of Iowa
- Number of pages
- xiv, 114 pages
- Copyright
- Copyright 2024 Gavin Riley McGivney
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Date submitted
- 12/07/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 98-114).
- Public Abstract (ETD)
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive, deadly sarcomas that development from cells surrounding nerves. MPNSTs have high recurrence and metastasis rates, making them difficult to treat. Despite surgical removal being the best option, therapeutic resistance remains a significant challenge. Unfortunately, little progress has been made in improving MPNST treatment over the past four decades. This underscores the urgent need for novel therapies. The goal of this work is to uncover unknown biological mechanisms that could inspire new treatment strategies.
Cancer cells often rewire their metabolism to support uncontrolled growth, yet little is understood about the metabolic rewiring that occurs in MPNSTs. In this study, I compared the metabolic impacts of losing two commonly mutated or lost tumor suppressor genes in MPNSTs, CDKN2A and TP53. Using a CRISPR/Cas9 mouse model and comprehensive molecular screening, I identified distinct metabolic pathways effected by the loss of these tumor suppressors. This led to the discovery of potential therapeutic targets for future treatment of MPNST. Human patient data further validated the upregulation of these pathways, supporting findings from the mouse model. Overall, this study highlights the metabolic vulnerabilities in MPNSTs and suggests potential therapeutic strategies, providing a foundation for future targeted treatments that could improve patient outcomes.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984774868002771
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