Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.
Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.
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DOI：
10.1007/s00401-018-1830-2
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发表时间：
2018-05
影响因子：
12.7
通讯作者：
Martinez-Barbera JP
中科院分区：
文献类型：
--
作者：
Apps JR;Carreno G;Gonzalez-Meljem JM;Haston S;Guiho R;Cooper JE;Manshaei S;Jani N;Hölsken A;Pettorini B;Beynon RJ;Simpson DM;Fraser HC;Hong Y;Hallang S;Stone TJ;Virasami A;Donson AM;Jones D;Aquilina K;Spoudeas H;Joshi AR;Grundy R;Storer LCD;Korbonits M;Hilton DA;Tossell K;Thavaraj S;Ungless MA;Gil J;Buslei R;Hankinson T;Hargrave D;Goding C;Andoniadou CL;Brogan P;Jacques TS;Williams HJ;Martinez-Barbera JP
Adamantinomatous颅咽管瘤（ACP）是临床上具有挑战性的肿瘤，其中大多数在CTNNB 1中具有激活突变。它们在组织学上是复杂的，显示出囊性和实性成分，后者由不同形态的细胞类型（例如β-连环蛋白聚集的簇细胞和栅栏上皮）组成，周围是与免疫细胞反应的华丽的胶质细胞。在这里，我们对18个ACP样本进行了RNA测序，并将这些数据与现有的ACP转录组数据集进行了整合。到目前为止，还没有研究检查肿瘤不同细胞区室中的基因表达模式。为了实现这一目标，我们将激光捕获显微切割与计算分析相结合，以揭示与上皮肿瘤细胞（簇和栅栏上皮），神经胶质组织或免疫浸润相关的基因组。我们使用来自两个ACP小鼠模型的这些人类ACP分子特征和RNA-Seq数据来揭示细胞簇在分子上类似于釉质结，釉质结是控制正常牙齿形态发生的关键信号中心。支持这一发现，我们表明，人类簇细胞表达高水平的几个成员的FGF，TGFB和BMP家族的分泌因子，信号到邻近的细胞证明了对磷酸化蛋白pERK 1/2，pSMAD 3和pSMAD 1/5/9在人类和小鼠ACP的免疫染色。我们发现，抑制MAPK/ERK途径与曲美替尼，临床批准的MEK抑制剂，结果在人和小鼠ACP外植体培养物的增殖减少和凋亡增加。最后，我们分析了胶质反应组织中的突出分子特征，以表征炎症微环境并揭示人类ACP中炎性小体的激活。我们通过对ACP患者的实体瘤和囊液中的免疫细胞标记物、细胞因子ELISA和蛋白质组分析进行免疫染色来验证这些结果。我们的数据支持一种新的分子模式，用于理解ACP肿瘤发生为天然牙齿发育的异常模拟，并通过揭示人类ACP中MAPK/ERK和炎性体通路的激活开辟了新的治疗机会。本文的在线版本（10.1007/s 00401 -018-1830-2）包含补充材料，可供授权用户使用。
Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP. The online version of this article (10.1007/s00401-018-1830-2) contains supplementary material, which is available to authorized users.
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影响因子：
6.4
作者：
Hoelsken, Annett;Kreutzer, Juergen;Buslei, Rolf
通讯作者：
Buslei, Rolf
影响因子：
1.1
作者：
Cao, J.;Lin, J. P.;Huang, Z. S.
通讯作者：
Huang, Z. S.
DOI：
10.1016/0030-4220(83)90098-1
发表时间：
1983-01-01
影响因子：
--
作者：
BERNSTEIN, ML;BUCHINO, JJ
通讯作者：
BUCHINO, JJ
影响因子：
4.6
作者：
Gritli-Linde, A;Bei, M;McMahon, AP
通讯作者：
McMahon, AP
影响因子：
5.8
作者：
Gomes, D. C.;Jamra, S. A.;Antonini, S. R.
通讯作者：
Antonini, S. R.