Hypoxia-associated factor expression in low-grade and anaplastic gliomas: a marker of poor outcome

International audienceSomatic mutations in isocitrate dehydrogenase (IDH) genes have recently been identified in a large proportion of glial tumors of the CNS and reported to be a strong prognostic factor in gliomas whatever the tumor grade. Few data are available in the literature regarding the relationship between IDH mutations and HIF expression in low-grade gliomas (LGGs), especially in a recently described aggressive molecular subtype: " triple negative " (IDH non mutated, 1p 19q non codeleted, p53 expression negative) gliomas. We analyzed clinical, radiological and molecular features of a series of 31 grade II/III gliomas. p53 expression, 1p19q deletion and IDH mutation status were provided for all tumors. Also HIF (hypoxia inducible factor)-1α, HIF-2α, HAF, Sox2 (SRY(Sex determining region Y)-box2) and OCT (octamer binding factor) 3/4 expressions were analyzed. We found positive HIF-2α staining in 38.7% of cases which was uncorrelated to HIF-1α expression or IDH1/2 mutation status. However, HIF-2α staining was significantly associated with HAF expression, a stem-like cell marker, in the whole population. HAF expression was present in 74.2% of cases and significantly correlated to Sox2 expression. Furthermore, HAF expression was significantly associated with the " triple negative " glioma phenotype. We provide here first evidence that HAF, a stem-like cell marker, expression is highly correlated to the triple negative aggressive LGG/AG molecular phenotype suggesting that these tumours might arise from cells of different origin

NKCC1 Regulates Migration Ability of Glioblastoma Cells by Modulation of Actin Dynamics and Interacting with Cofilin

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The mechanisms that confer GBM cells their invasive behavior are poorly understood. The electroneutral Na+-K+-2Cl− co-transporter 1 (NKCC1) is an important cell volume regulator that participates in cell migration. We have shown that inhibition of NKCC1 in GBM cells leads to decreased cell migration, in vitro and in vivo. We now report on the role of NKCC1 on cytoskeletal dynamics. We show that GBM cells display a significant decrease in F-actin content upon NKCC1 knockdown (NKCC1-KD). To determine the potential actin-regulatory mechanisms affected by NKCC1 inhibition, we studied NKCC1 protein interactions. We found that NKCC1 interacts with the actin-regulating protein Cofilin-1 and can regulate its membrane localization. Finally, we analyzed whether NKCC1 could regulate the activity of the small Rho-GTPases RhoA and Rac1. We observed that the active forms of RhoA and Rac1 were decreased in NKCC1-KD cells. In summary, we report that NKCC1 regulates GBM cell migration by modulating the cytoskeleton through multiple targets including F-actin regulation through Cofilin-1 and RhoGTPase activity. Due to its essential role in cell migration NKCC1 may serve as a specific therapeutic target to decrease cell invasion in patients with primary brain cancer

Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

Summary: Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors. : Malignant neoplasms exhibit uninhibited and dysregulated growth coupled with acquisition of stem-like properties that are integral to the development and progression of disease. Shah et al. demonstrate a critical role of brachyury in regulating stemness and growth by activating YAP through direct transcriptional and post-transcriptional mechanisms in various cancers. Keywords: brachyury, YAP, chordoma, stremness, growth, glioblastoma, lung carcinom