Jo Hanhee, Dalvi Aneesh, Yang Wenqi, Morozova Elizabeth, Munoz Sarah, Glasgow Stacey M
Neurobiology Department, School of Biological Sciences, University of California San Diego, La Jolla, 92093 CA, USA.
Neurosciences Graduate Program, University of California San Diego, La Jolla, 92093 CA, USA.
bioRxiv. 2025 Jan 2:2024.12.31.630965. doi: 10.1101/2024.12.31.630965.
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 and 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.
多形性胶质母细胞瘤（GBM）是成人脑癌中最常见且恶性程度很高的一种，其总体生存率较低。有效的治疗方式仍然有限，因此有必要寻找新的治疗方法。神经发育途径与胶质瘤的形成有关，关键的神经发育调节因子在胶质瘤发生过程中会重新表达或被选用。在此，我们确定丝氨酸/苏氨酸激酶NUAK家族激酶2（NUAK2）是小鼠和人类大脑中的一种胎儿癌基因。我们发现NUAK2在胚胎大脑中大量表达，在出生后各阶段表达量下降，然后在恶性胶质瘤中重新表达。然而，NUAK2在GBM发生中的作用仍不清楚。我们证明，在GBM细胞中，CRIPSR-Cas9介导的NUAK2缺失会导致增殖受到抑制，而在体外和体内模型中过表达则会导致细胞生长增强。对在没有NUAK2的情况下失调的下游生物学过程的进一步研究表明，NUAK2调节细胞外基质（ECM）成分以促进迁移行为。最后，我们确定对NUAK2的药物抑制足以阻碍恶性胶质瘤细胞的增殖和迁移。我们的结果表明，NUAK2是GBM治疗的一个可行治疗靶点。
