Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype.
Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype.
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DOI：
10.1016/j.celrep.2016.06.058
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发表时间：
2016-07-26
期刊：
影响因子：
8.8
通讯作者：
Alman BA
中科院分区：
文献类型：
--
作者：
Sato S;Tang YJ;Wei Q;Hirata M;Weng A;Han I;Okawa A;Takeda S;Whetstone H;Nadesan P;Kirsch DG;Wunder JS;Alman BA
大多数间叶性肿瘤的起源细胞尚不清楚。促成该谱系的一种细胞类型是周细胞，一种表达 Ng2/Cspg4 的细胞。通过谱系追踪，我们证明由Trp53肿瘤抑制基因缺失驱动的骨和软组织肉瘤，或由Apc突变驱动的硬纤维瘤可以源自表达Ng2/Cspg4的细胞。这些细胞中Trp53肿瘤抑制基因的缺失导致了与人类肉瘤非常相似的骨和软组织肉瘤，而在同一细胞类型中稳定β-连环蛋白则导致了硬纤维瘤。比较表达缺乏 Trp53 的 Ng2/Cspg4 周细胞和因删除 Trp53 引起的肉瘤之间的表达，结果显示肉瘤中 β-连环蛋白信号传导受到抑制。 β-连环蛋白的激活抑制肉瘤的形成和生长。因此，周细胞可能是间充质肿瘤的起源细胞，β-连环蛋白失调在肿瘤表型中起着重要作用。在这里，我们使用小鼠的谱系追踪研究表明，由 Trp53 肿瘤抑制基因缺失驱动的骨和软组织肉瘤可以源自表达 Ng2/Cspg4 的周细胞。由 Apc 突变驱动的良性间叶硬纤维瘤可能源自表达 Ng2/Cspg4 的细胞。 Ng2/Cspg4 表达细胞中 Trp53 或 β-catenin 的驱动突变导致肉瘤或硬纤维瘤形成。比较表达缺乏 Trp53 的 Ng2/Cspg4 周细胞和删除 Trp53 产生的肉瘤之间的 RNA 测序表达谱，结果显示肉瘤中 β-连环蛋白信号传导受到抑制。 β-连环蛋白的激活抑制肉瘤的形成和生长。我们的数据表明，周细胞可能是间叶性肿瘤的起源细胞。此外，β-连环蛋白在间叶性肿瘤中起着至关重要的作用，恶性肉瘤表现出较低水平的β-连环蛋白活性。
The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing β-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4 expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53, showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and β-catenin dysregulation plays an important role in the neoplastic phenotype. Here we used lineage tracing studies in mice to show that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor gene, can derive from Ng2/Cspg4 expressing pericytes. Benign mesenchymal desmoid tumors, driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Driving mutations in Trp53 or β-catenin in Ng2/Cspg4 expressing cells, resulted in sarcoma or desmoid tumor formation. Comparing the expression profiles from RNA sequencing between Ng2/Cspg4 expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53, showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Our data shows that pericytes can be a cell of origin for mesenchymal tumors. Furthermore, β-catenin plays a critical role in mesenchymal neoplasia, with malignant sarcomas exhibiting a lower level of lower level of β-catenin activity.