Morozova, E. | bioRxiv Science

bioRxiv2025

A fetal oncogene NUAK2 is an emerging therapeutic target in glioblastoma.

Glioblastoma Multiforme (GBM) is the most prevalent and highly malignant form of adult brain cancer characterized by poor overall survival rates. Effective therapeutic modalities remain limited, necessitating the search for novel treatments. Neurodevelopmental pathways have been implicated in glioma formation, with key neurodevelopmental regulators being re- expressed or co-opted during glioma tumorigenesis. Here we identified a serine/threonine kinase, NUAK family kinase 2 (NUAK2), as a fetal oncogene in mouse and human brains. We found robust expression of NUAK2 in the embryonic brain that decreases throughout postnatal stages and then is re-expressed in malignant gliomas. However, the role of NUAK2 in GBM tumorigenesis remains unclear. We demonstrate that CRIPSR-Cas9 mediated NUAK2 deletion in GBM cells results in suppression of proliferation, while overexpression leads to enhanced cell growth in both in vitro and in vivo models. Further investigation of the downstream biological processes dysregulated in the absence of NUAK2 reveals that NUAK2 modulates extracellular matrix (ECM) components to facilitate migratory behavior. Lastly, we determined that pharmaceutical inhibition of NUAK2 is sufficient to impede the proliferation and migration of malignant glioma cells. Our results suggest that NUAK2 is an actionable therapeutic target for GBM treatment.

cell biology↗

bioRxiv2017

Circuit-level Mechanisms of EtOH-dependent dopamine release.

Alcoholism is the third leading cause of preventable mortality in the world. In the last decades a large body of experimental data has paved the way to a clearer knowledge of the specific molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms play together to result in a dysregulated dopamine (DA) release under alcohol influence remains unclear. In this manuscript, we delineate potential circuit-level mechanisms responsible for EtOH-dependent increase and dysregulation of DA release from the ventral tegmental area (VTA) into nucleus accumbens (Nac). For this purpose, we build a circuit model of the VTA composed of DA and GABAergic neurons, that integrate external Glutamatergic (Glu) inputs to result in DA release. In particular, we reproduced a non-monotonic dose dependence of DA neurons firing activity on EtOH: an increase in firing at small to intermediate doses and a drop below baseline (alcohol-free) levels at high EtOH concentrations. Our simulations predict that a certain level of synchrony is necessary for the firing rate increase produced by EtOH. Moreover, EtOHs effect on the DA neurons firing rate and, consequently, DA release can reverse depending on the average activity level of the Glu afferents to VTA. Further, we propose a mechanism for emergence of transient (phasic) DA peaks and the increase in their frequency in EtOH. Phasic DA transients result from DA neuron population bursts, and these bursts are enhanced in EtOH. These results suggest the role of synchrony and average activity level of Glu afferents to VTA in shaping the phasic and tonic DA release under the acute influence of EtOH and in normal conditions.

neuroscience↗