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000132879 0247_ $$2doi$$a10.1007/s00401-018-1830-2
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000132879 0247_ $$2pmc$$apmc:PMC5904225
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000132879 0247_ $$2ISSN$$a1432-0533
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000132879 037__ $$aDKFZ-2018-00521
000132879 041__ $$aeng
000132879 082__ $$a610
000132879 1001_ $$aApps, John R$$b0
000132879 245__ $$aTumour 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.
000132879 260__ $$aBerlin$$bSpringer$$c2018
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000132879 520__ $$aAdamantinomatous 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.
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000132879 7001_ $$aCarreno, Gabriela$$b1
000132879 7001_ $$aGonzalez-Meljem, Jose Mario$$b2
000132879 7001_ $$aHaston, Scott$$b3
000132879 7001_ $$aGuiho, Romain$$b4
000132879 7001_ $$aCooper, Julie E$$b5
000132879 7001_ $$aManshaei, Saba$$b6
000132879 7001_ $$aJani, Nital$$b7
000132879 7001_ $$aHölsken, Annett$$b8
000132879 7001_ $$aPettorini, Benedetta$$b9
000132879 7001_ $$aBeynon, Robert J$$b10
000132879 7001_ $$aSimpson, Deborah M$$b11
000132879 7001_ $$aFraser, Helen C$$b12
000132879 7001_ $$aHong, Ying$$b13
000132879 7001_ $$aHallang, Shirleen$$b14
000132879 7001_ $$aStone, Thomas J$$b15
000132879 7001_ $$aVirasami, Alex$$b16
000132879 7001_ $$aDonson, Andrew M$$b17
000132879 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b18$$udkfz
000132879 7001_ $$aAquilina, Kristian$$b19
000132879 7001_ $$aSpoudeas, Helen$$b20
000132879 7001_ $$aJoshi, Abhijit R$$b21
000132879 7001_ $$aGrundy, Richard$$b22
000132879 7001_ $$aStorer, Lisa C D$$b23
000132879 7001_ $$aKorbonits, Márta$$b24
000132879 7001_ $$aHilton, David A$$b25
000132879 7001_ $$aTossell, Kyoko$$b26
000132879 7001_ $$aThavaraj, Selvam$$b27
000132879 7001_ $$aUngless, Mark A$$b28
000132879 7001_ $$aGil, Jesus$$b29
000132879 7001_ $$aBuslei, Rolf$$b30
000132879 7001_ $$aHankinson, Todd$$b31
000132879 7001_ $$aHargrave, Darren$$b32
000132879 7001_ $$aGoding, Colin$$b33
000132879 7001_ $$aAndoniadou, Cynthia L$$b34
000132879 7001_ $$aBrogan, Paul$$b35
000132879 7001_ $$aJacques, Thomas S$$b36
000132879 7001_ $$aWilliams, Hywel J$$b37
000132879 7001_ $$00000-0002-5292-7276$$aMartinez-Barbera, Juan Pedro$$b38
000132879 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-018-1830-2$$gVol. 135, no. 5, p. 757 - 777$$n5$$p757 - 777$$tActa neuropathologica$$v135$$x1432-0533$$y2018
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000132879 9141_ $$y2018
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