Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.
Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.
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DOI：
10.1038/s41467-023-38432-6
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发表时间：
2023-05-10
影响因子：
16.6
通讯作者：
Zadeh, Gelareh
中科院分区：
文献类型：
--
作者：
Suppiah, Suganth;Mansouri, Sheila;Mamatjan, Yasin;Liu, Jeffrey C.;Bhunia, Minu M.;Patil, Vikas;Rath, Prisni;Mehani, Bharati;Heir, Pardeep;Bunda, Severa;Velez-Reyes, German L.;Singh, Olivia;Ijad, Nazanin;Pirouzmand, Neda;Dalcourt, Tatyana;Meng, Ying;Karimi, Shirin;Wei, Qingxia;Nassiri, Farshad;Pugh, Trevor J.;Bader, Gary D.;Aldape, Kenneth D.;Largaespada, David A.;Zadeh, Gelareh
恶性周围神经鞘瘤（MPNST）是一种高度侵袭性的肉瘤，是一种致死性1型神经纤维瘤病相关的恶性肿瘤，在治疗策略方面进展甚微。在这里，我们对108个肿瘤进行了多平台综合分子分析，以确定可以作为治疗靶点的MPNST候选驱动因素。对甲基组和转录组谱的无监督分析确定了两个不同的mpnst亚群，它们具有独特的靶向致癌程序。我们建立了两个MPNSTs亚群：MPNST-G1中的SHH通路激活和MPNST-G2中的WNT/ß-catenin/CCND1通路激活。单核RNA测序表征了复杂的细胞结构，并表明来自MPNST-G1和MPNST-G2的恶性细胞分别具有神经冠样和雪旺细胞前体样细胞特征。此外，在MPNST的临床前模型中，我们证实抑制MPNST- g1中的SHH通路可以阻止生长和恶性进展，为在临床试验中研究这些治疗方法提供了依据。恶性周围神经鞘肿瘤是一种侵袭性肉瘤，治疗选择有限。在这里，作者利用DNA甲基化和转录组学数据来鉴定两种具有潜在治疗脆弱性的肿瘤亚型。
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials. Malignant peripheral nerve sheath tumours are an aggressive form of sarcoma, with limited treatment options. Here, the authors utilise DNA methylation and transcriptomic data to identify two subtypes of tumours with potential therapeutic vulnerabilities.
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