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体细胞CRISPR肿瘤发生及多组学分析揭示了MPNST中磷酸戊糖途径破坏的易感性。

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

作者信息

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

机构信息

Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.

Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.

出版信息

Sci Adv. 2025 Aug 15;11(33):eadu2906. doi: 10.1126/sciadv.adu2906. Epub 2025 Aug 13.

DOI:10.1126/sciadv.adu2906
PMID:40802750
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12346278/
Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor survival rates. Loss of or 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 - versus -deleted MPNSTs. Convergent, multiomic analyses revealed that -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 -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 -deleted majority.

摘要

恶性外周神经鞘瘤（MPNSTs）是侵袭性强且对化疗耐药的肉瘤，生存率低。NF1缺失或破坏后缺失是MPNST发生发展的关键事件。在此，我们利用小鼠中的CRISPR-Cas9体细胞肿瘤发生技术来鉴定区分NF1缺失型与非缺失型MPNST的转录组学和代谢组学特征。趋同的多组学分析表明，NF1缺失型MPNST在生长和生存能力方面特别依赖磷酸戊糖途径（PPP）和NADPH代谢。磷酸戊糖途径限速酶葡萄糖-6-磷酸脱氢酶（G6PD）的破坏减缓了NF1缺失型MPNST的生长，并使MPNST对标准护理化疗敏感。氧化还原调节转录因子NRF2的敲低减缓了MPNST的生长并降低了G6PD的转录。对患者MPNST的分析确定了与肿瘤转化相关的NRF2基因特征。此外，泛癌TCGA样本中的G6PD和NRF2表达与患者生存率相关。这项工作确定NRF2-PPP依赖性是这些难以治疗的MPNST中一个可靶向的脆弱点，特别是在NF1缺失的大多数病例中。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/1daa99a9b3af/sciadv.adu2906-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/815fac5fd3a5/sciadv.adu2906-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/98370b5a62f7/sciadv.adu2906-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/da57d0740231/sciadv.adu2906-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/e311ef31b044/sciadv.adu2906-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/8670c6002ce4/sciadv.adu2906-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/1daa99a9b3af/sciadv.adu2906-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/815fac5fd3a5/sciadv.adu2906-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/98370b5a62f7/sciadv.adu2906-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/da57d0740231/sciadv.adu2906-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/e311ef31b044/sciadv.adu2906-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/8670c6002ce4/sciadv.adu2906-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73df/12346278/1daa99a9b3af/sciadv.adu2906-f6.jpg

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本文引用的文献

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2
Carfilzomib activates ER stress and JNK/p38 MAPK signaling to promote apoptosis in hepatocellular carcinoma cells.卡非佐米通过激活内质网应激和 JNK/p38 MAPK 信号通路促进肝癌细胞凋亡。
Acta Biochim Biophys Sin (Shanghai). 2024 May 25;56(5):697-708. doi: 10.3724/abbs.2024040.
3
Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis.
恶性外周神经鞘膜瘤细胞系的深度基因组分析对当前恶性外周神经鞘膜瘤的诊断提出了挑战。
iScience. 2023 Jan 31;26(2):106096. doi: 10.1016/j.isci.2023.106096. eCollection 2023 Feb 17.
4
Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.恶性外周神经鞘瘤（MPNST）进化的基因组模式与临床结果相关，并可在无细胞 DNA 中检测到。
Cancer Discov. 2023 Mar 1;13(3):654-671. doi: 10.1158/2159-8290.CD-22-0786.
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