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000125312 1001_ $$00000-0002-5016-8202$$aJung, Erik$$b0$$eFirst author
000125312 245__ $$aTweety-Homolog 1 Drives Brain Colonization of Gliomas.
000125312 260__ $$aWashington, DC$$bSoc.$$c2017
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000125312 520__ $$aEarly 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.
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000125312 7001_ $$0P:(DE-He78)e5e541194cff586d79a62f992420e0c5$$aOsswald, Matthias$$b1
000125312 7001_ $$0P:(DE-He78)e9a2788d72412f2864cee1ff0cd6b3ca$$aBlaes, Jonas$$b2$$udkfz
000125312 7001_ $$aWiestler, Benedikt$$b3
000125312 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b4
000125312 7001_ $$0P:(DE-He78)e189ca62582a66917b44b270e71f8f2a$$aSchmenger, Torsten$$b5$$udkfz
000125312 7001_ $$aSolecki, Gergely$$b6
000125312 7001_ $$0P:(DE-He78)c1a5de00fb2617c5c43d8f30f6e0cd2b$$aDeumelandt, Katrin$$b7$$udkfz
000125312 7001_ $$aKurz, Felix T$$b8
000125312 7001_ $$0P:(DE-He78)07de1c0592124175413da2fb91f61b5a$$aXie, Ruifan$$b9$$udkfz
000125312 7001_ $$0P:(DE-He78)40d033fc1ce702c778d45aaa3d29a2d7$$aWeil, Sophie$$b10$$udkfz
000125312 7001_ $$00000-0003-0229-5810$$aHeil, Oliver$$b11
000125312 7001_ $$0P:(DE-He78)b759df221730b38264f533848f4bed4a$$aThomé, Carina$$b12
000125312 7001_ $$aGömmel, Miriam$$b13
000125312 7001_ $$0P:(DE-He78)da492d7c5716866dda3d1feb263f4cca$$aSyed, Mustafa$$b14$$udkfz
000125312 7001_ $$aHäring, Peter$$b15
000125312 7001_ $$0P:(DE-He78)3291aaac20f3d603d96744c1f0890028$$aHuber, Peter$$b16
000125312 7001_ $$00000-0002-2796-3451$$aHeiland, Sabine$$b17
000125312 7001_ $$0P:(DE-He78)5ef8651b0f857b9c640aa5b1498c43b5$$aPlatten, Michael$$b18
000125312 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b19
000125312 7001_ $$0P:(DE-He78)92e9783ca7025f36ce14e12cd348d2ee$$aWick, Wolfgang$$b20
000125312 7001_ $$0P:(DE-He78)6c294453ee36ad59deddc5494fa6aa4b$$aWinkler, Frank$$b21$$eLast author
000125312 773__ $$0PERI:(DE-600)1475274-8$$a10.1523/JNEUROSCI.3532-16.2017$$gVol. 37, no. 29, p. 6837 - 6850$$n29$$p6837 - 6850$$tThe journal of neuroscience$$v37$$x0270-6474$$y2017
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