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@ARTICLE{Apps:132879,
      author       = {J. R. Apps and G. Carreno and J. M. Gonzalez-Meljem and S.
                      Haston and R. Guiho and J. E. Cooper and S. Manshaei and N.
                      Jani and A. Hölsken and B. Pettorini and R. J. Beynon and
                      D. M. Simpson and H. C. Fraser and Y. Hong and S. Hallang
                      and T. J. Stone and A. Virasami and A. M. Donson and D.
                      Jones$^*$ and K. Aquilina and H. Spoudeas and A. R. Joshi
                      and R. Grundy and L. C. D. Storer and M. Korbonits and D. A.
                      Hilton and K. Tossell and S. Thavaraj and M. A. Ungless and
                      J. Gil and R. Buslei and T. Hankinson and D. Hargrave and C.
                      Goding and C. L. Andoniadou and P. Brogan and T. S. Jacques
                      and H. J. Williams and J. P. Martinez-Barbera},
      title        = {{T}umour 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.},
      journal      = {Acta neuropathologica},
      volume       = {135},
      number       = {5},
      issn         = {1432-0533},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2018-00521},
      pages        = {757 - 777},
      year         = {2018},
      abstract     = {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.},
      cin          = {B062},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29541918},
      pmc          = {pmc:PMC5904225},
      doi          = {10.1007/s00401-018-1830-2},
      url          = {https://inrepo02.dkfz.de/record/132879},
}