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J Neurosci. 2017 Jul 19;37(29):6837-6850. doi: 10.1523/JNEUROSCI.3532-16.2017. Epub 2017 Jun 12.

Tweety-Homolog 1 Drives Brain Colonization of Gliomas.

Author information

1
Neurology Clinic and National Center for Tumor Diseases.
2
Clinical Cooperation Unit Neurooncology, German Cancer Consortium.
3
Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar der Technischen Universität München, 81675 Munich, Germany.
4
Clinical Cooperation Unit Neuropathology, German Cancer Consortium.
5
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, 69120 Heidelberg, Germany, and.
6
Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium.
7
Department of Neuroradiology, and.
8
Genomics and Proteomics Core Facility.
9
Department of Radiation Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
10
Department of Medical Physics, and.
11
Clinical Cooperation Unit Molecular and Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany.
12
Department of Neurology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany.
13
Neurology Clinic and National Center for Tumor Diseases, frank.winkler@med.uni-heidelberg.de.

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.

KEYWORDS:

Ttyh1; glioblastoma; glioma; invasion; migration; tumor microtubes

PMID:
28607172
PMCID:
PMC6705725
DOI:
10.1523/JNEUROSCI.3532-16.2017
[Indexed for MEDLINE]
Free PMC Article

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