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@ARTICLE{Westphal:212545,
      author       = {D. Westphal and M. Meinhardt and K. Grützmann and L.
                      Schöne and J. Steininger and L. T. Neuhaus and M. Wiegel
                      and D. Schrimpf$^*$ and D. E. Aust$^*$ and E. Schröck and
                      G. B. Baretton$^*$ and S. Beissert and T. A. Juratli and G.
                      G. Schackert and J. Gravemeyer$^*$ and J. Becker$^*$ and A.
                      von Deimling$^*$ and C. Koelsche$^*$ and B. Klink and F.
                      Meier and A. Schulz and M. H. Muders and M. Seifert},
      title        = {{I}dentification of epigenetically regulated genes
                      distinguishing intracranial from extracranial melanoma
                      metastases.},
      journal      = {The journal of investigative dermatology},
      volume       = {143},
      number       = {7},
      issn         = {0022-202x},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-00230},
      pages        = {1233-1245.e17},
      year         = {2023},
      note         = {2023 Jul;143(7):1233-1245.e17},
      abstract     = {Despite remarkable advances in treating patients with
                      metastatic melanoma, management of melanoma brain metastases
                      remains challenging. Recent evidence suggests that
                      epigenetic reprogramming is an important mechanism for the
                      adaptation of melanoma cells to the brain environment. In
                      this study, methylomes and transcriptomes of a cohort of
                      matched melanoma metastases were evaluated by integrated
                      omics data analysis. The identified 38 candidate genes
                      displayed distinct promoter methylation and corresponding
                      gene expression changes in intracranial compared to
                      extracranial metastases. The 11 most promising genes were
                      validated on protein level in both tumor and surrounding
                      normal tissue using immunohistochemistry. For 8 of them,
                      STK10, PDXK, WDR24, CSPP1, NMB, RASL11B, pPRKCZ/PRKCZ,
                      pGRB10, a significantly different protein expression in
                      intracranial versus extracranial metastases was confirmed in
                      accordance with the underlying promoter methylation and gene
                      expression changes. The observed changes imply a distinct
                      intracranial phenotype with increased AKT phosphorylation
                      and higher frequency of proliferating cells. Knockdown of
                      PRKCZ or GRB10 altered the expression of pAKT and decreased
                      the viability of a brain-specific melanoma cell line. In
                      summary, epigenetically regulated cancer-relevant
                      alterations were identified, that provide insights into the
                      molecular mechanisms that discriminate brain from other
                      organ metastases, which could be exploited by targeting the
                      affected signaling pathways.},
      keywords     = {Melanoma metastases (Other) / extracranial metastases
                      (Other) / gene expression (Other) / intracranial metastases
                      (Other) / promoter methylation (Other)},
      cin          = {B300 / HD01 / DD01 / ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)B300-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)DD01-20160331 / I:(DE-He78)ED01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36716920},
      doi          = {10.1016/j.jid.2023.01.011},
      url          = {https://inrepo02.dkfz.de/record/212545},
}