多组学分析揭示了多梳抑制复合物2在施万细胞系和恶性外周神经鞘瘤中的新靶点。

Multiomic analyses reveal new targets of polycomb repressor complex 2 in Schwann lineage cells and malignant peripheral nerve sheath tumors.

作者信息

Bhunia Minu M, Stehn Christopher M, Jubenville Tyler A, Novacek Ethan L, Larsson Alex T, Madala Mahathi, Suppiah Suganth, Velez-Reyes Germán L, Williams Kyle B, Sokolowski Mark, Williams Rory L, Finnerty Samuel J, Temiz Nuri A, Caride Ariel, Bhagwate Aditya V, Nagaraj Nagaswaroop K, Lee Jeong-Heon, Ordog Tamas, Zadeh Gelareh, Largaespada David A

机构信息

Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota, USA.

Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

出版信息

Neurooncol Adv. 2024 Nov 9;6(1):vdae188. doi: 10.1093/noajnl/vdae188. eCollection 2024 Jan-Dec.

DOI:10.1093/noajnl/vdae188

PMID:39620202

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11606644/

Abstract

BACKGROUND

Malignant peripheral nerve sheath tumors (MPNSTs) can arise from atypical neurofibromas (ANF). Loss of the polycomb repressor complex 2 (PRC2) is a common event. Previous studies on PRC2-regulated genes in MPNST used genetic add-back experiments in highly aneuploid MPNST cell lines which may miss PRC2-regulated genes in -mutant ANF-like precursor cells. A set of PRC2-regulated genes in human Schwann cells (SCs) has not been defined. We hypothesized that PRC2 loss has direct and indirect effects on gene expression resulting in MPNST, so we sought to identify PRC2-regulated genes in immortalized human Schwann cells (iHSCs).

METHODS

We engineered -deficient iHSCs with loss of function or mutations. RNA sequencing revealed 1327 differentially expressed genes to define PRC2-regulated genes. To investigate MPNST pathogenesis, we compared genes in iHSCs to consistent gene expression differences between ANF and MPNSTs. Chromatin immunoprecipitation sequencing was used to further define targets. Methylome and proteomic analyses were performed to further identify enriched pathways.

RESULTS

We identified potential PRC2-regulated drivers of MPNST progression. Pathway analysis indicates many upregulated cancer-related pathways. We found transcriptional evidence for activated Notch and Sonic Hedgehog (SHH) signaling in PRC2-deficient iHSCs. Functional studies confirm that Notch signaling is active in MPNST cell lines, patient-derived xenografts, and transient cell models of PRC2 deficiency. A combination of MEK and γ-secretase inhibition shows synergy in MPNST cell lines.

CONCLUSIONS

We identified PRC2-regulated genes and potential drivers of MPNSTs. Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

摘要

背景

恶性外周神经鞘瘤（MPNSTs）可起源于非典型神经纤维瘤（ANF）。多梳抑制复合物2（PRC2）功能缺失是常见现象。以往关于MPNST中PRC2调控基因的研究采用了高度非整倍体MPNST细胞系中的基因回补实验，这可能会遗漏突变的ANF样前体细胞中的PRC2调控基因。人类雪旺细胞（SCs）中一组PRC2调控基因尚未明确。我们推测PRC2缺失对基因表达有直接和间接影响，从而导致MPNST，因此我们试图在永生化人类雪旺细胞（iHSCs）中鉴定PRC2调控基因。

方法

我们构建了功能缺失或突变的PRC2缺陷型iHSCs。RNA测序揭示了1327个差异表达基因，以确定PRC2调控基因。为研究MPNST的发病机制，我们将iHSCs中的基因与ANF和MPNST之间一致的基因表达差异进行比较。染色质免疫沉淀测序用于进一步确定靶点。进行甲基化组和蛋白质组分析以进一步鉴定富集通路。

结果

我们鉴定出了MPNST进展中潜在的PRC2调控驱动因子。通路分析表明许多癌症相关通路上调。我们在PRC2缺陷型iHSCs中发现了Notch和音猬因子（SHH）信号激活的转录证据。功能研究证实Notch信号在MPNST细胞系、患者来源的异种移植瘤以及PRC2缺陷的瞬时细胞模型中均有活性。MEK和γ-分泌酶抑制剂联合使用在MPNST细胞系中显示出协同作用。