Tweety-Homolog 1 Drives Brain Colonization of Gliomas

Abstract

Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. We recently discovered ultralong (Ͼ10 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.

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

“…Our interest in the Ttyh family members stemmed from previous works in which Ttyh2 was identified as a gene upregulated in renal and colon cancers [9,11], implicating Ttyh as a potent regulator of cell proliferation. Recently, this hypothesis was further supported by a study reporting that Ttyh1 was important for glioma growth and Ttyh1 downregulation resulted in reduced tumor progression [12]. More relevant to our study, Ttyh1 was found to be strongly expressed in the ventricular zone (VZ) [13][14][15], where neural stem cells reside and active cell proliferation occurs in the mammalian developing brain.…”

Neuronal activity in the glioma microenvironment

“…In addition to the previously described feed-forward expression of NLGN3 , several glutamate receptor subunit genes and the BDNF receptor gene NTRK2 increase expression following NLGN3 exposure in glioma (Venkatesh et al, 2017). As well, NLGN3 induces tweety homologue-1 ( TTHY1 ) expression, a protein that regulates tumor microtube network formation in glioma (Osswald et al, 2015; Jung et al, 2017). While the functional significance of these gene expression changes remain to be clarified, the complex downstream consequences of activity-regulated neuroligin-3 release in the tumor microenvironment indicate that our understanding is still nascent regarding this crucial molecule and its pathological roles in glioma.…”

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

“…Genes involved in cell proliferation were upregulated, as were numerous genes known to promote malignancy in glioma, including PDGFA 8–10 , TTYH1 11 and several potassium channel genes 12 (Extended Data Fig. 3).…”