RT Journal Article
SR Electronic
T1 Tweety-homologue 1 drives brain colonization of gliomas
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3532-16
DO 10.1523/JNEUROSCI.3532-16.2017
A1 Erik Jung
A1 Matthias Osswald
A1 Jonas Blaes
A1 Benedikt Wiestler
A1 Felix Sahm
A1 Torsten Schmenger
A1 Gergely Solecki
A1 Katrin Deumelandt
A1 Felix T. Kurz
A1 Ruifan Xie
A1 Sophie Weil
A1 Oliver Heil
A1 Carina Thomé
A1 Miriam Gömmel
A1 Mustafa Syed
A1 Peter Häring
A1 Peter E. Huber
A1 Sabine Heiland
A1 Michael Platten
A1 Andreas von Deimling
A1 Wolfgang Wick
A1 Frank Winkler
YR 2017
UL http://www.jneurosci.org/content/early/2017/06/08/JNEUROSCI.3532-16.2017.abstract
AB Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. Recently we have discovered ultra-long (> ten to hundreds of microns) membrane protrusions (tumor microtubes, TMs) that are extended by glioma cells. TMs were associated with the capacity of glioma cells to effectively invade the brain, and proliferate. Moreover, TMs were 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 central nervous system development. Among the highest scoring genes was tweety-homologue 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, 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 of 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 STATEMENTIn this report, we identify tweety-homologue 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.