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@ARTICLE{Jung:125312,
      author       = {E. Jung$^*$ and M. Osswald$^*$ and J. Blaes$^*$ and B.
                      Wiestler and F. Sahm$^*$ and T. Schmenger$^*$ and G. Solecki
                      and K. Deumelandt$^*$ and F. T. Kurz and R. Xie$^*$ and S.
                      Weil$^*$ and O. Heil$^*$ and C. Thomé$^*$ and M. Gömmel
                      and M. Syed$^*$ and P. Häring and P. Huber$^*$ and S.
                      Heiland and M. Platten$^*$ and A. von Deimling$^*$ and W.
                      Wick$^*$ and F. Winkler$^*$},
      title        = {{T}weety-{H}omolog 1 {D}rives {B}rain {C}olonization of
                      {G}liomas.},
      journal      = {The journal of neuroscience},
      volume       = {37},
      number       = {29},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.},
      reportid     = {DKFZ-2017-01445},
      pages        = {6837 - 6850},
      year         = {2017},
      abstract     = {Early and progressive colonization of the healthy brain is
                      one hallmark of diffuse gliomas, including glioblastomas. We
                      recently discovered ultralong (>10 to hundreds of microns)
                      membrane protrusions [tumor microtubes (TMs)] extended by
                      glioma cells. TMs have been associated with the capacity of
                      glioma cells to effectively invade the brain and
                      proliferate. Moreover, TMs are also used by some tumor cells
                      to interconnect to one large, resistant multicellular
                      network. Here, we performed a correlative gene-expression
                      microarray and in vivo imaging analysis, and identified
                      novel molecular candidates for TM formation and function.
                      Interestingly, these genes were previously linked to normal
                      CNS development. One of the genes scoring highest in tests
                      related to the outgrowth of TMs was tweety-homolog 1
                      (TTYH1), which was highly expressed in a fraction of TMs in
                      mice and patients. Ttyh1 was confirmed to be a potent
                      regulator of normal TM morphology and of TM-mediated
                      tumor-cell invasion and proliferation. Glioma cells with one
                      or two TMs were mainly responsible for effective brain
                      colonization, and Ttyh1 downregulation particularly affected
                      this cellular subtype, resulting in reduced tumor
                      progression and prolonged survival of mice. The remaining
                      Ttyh1-deficient tumor cells, however, had more
                      interconnecting TMs, which were associated with increased
                      radioresistance in those small tumors. These findings imply
                      a cellular and molecular heterogeneity in gliomas regarding
                      formation and function of distinct TM subtypes, with
                      multiple parallels to neuronal development, and suggest that
                      Ttyh1 might be a promising target to specifically reduce
                      TM-associated brain colonization by glioma cells in
                      patients.SIGNIFICANCE STATEMENT In this report, we identify
                      tweety-homolog 1 (Ttyh1), a membrane protein linked to
                      neuronal development, as a potent driver of tumor microtube
                      (TM)-mediated brain colonization by glioma cells. Targeting
                      of Ttyh1 effectively inhibited the formation of invasive TMs
                      and glioma growth, but increased network formation by
                      intercellular TMs, suggesting a functional and molecular
                      heterogeneity of the recently discovered TMs with potential
                      implications for future TM-targeting strategies.},
      cin          = {G370 / G380 / L101 / G160 / W110 / E055},
      ddc          = {610},
      cid          = {I:(DE-He78)G370-20160331 / I:(DE-He78)G380-20160331 /
                      I:(DE-He78)L101-20160331 / I:(DE-He78)G160-20160331 /
                      I:(DE-He78)W110-20160331 / I:(DE-He78)E055-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28607172},
      doi          = {10.1523/JNEUROSCI.3532-16.2017},
      url          = {https://inrepo02.dkfz.de/record/125312},
}