AUTHOR=Kałuzińska-Kołat Żaneta , Kołat Damian , Kośla Katarzyna , Płuciennik Elżbieta , Bednarek Andrzej K. 

TITLE=Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

JOURNAL=Frontiers in Neuroscience

VOLUME=17

YEAR=2023

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1260409

DOI=10.3389/fnins.2023.1260409

ISSN=1662-453X

ABSTRACT=<sec id="sec1"><title>Introduction</title><p>Glioblastoma (GBM) is notorious for its clinical and molecular heterogeneity, contributing to therapeutic failure and a grim prognosis. <italic>WWOX</italic> is one of the tumor suppressor genes important in nervous tissue or related pathologies, which was scarcely investigated in GBM for reliable associations with prognosis or disease progression despite known alterations. Recently, we observed a phenotypic heterogeneity between GBM cell lines (U87MG, T98G, U251MG, DBTRG-05MG), among which the anti-GBM activity of <italic>WWOX</italic> was generally corresponding, but colony growth and formation were inconsistent in DBTRG-05MG. This prompted us to investigate the molecular landscapes of these cell lines, intending to translate them into the clinical context.</p></sec><sec id="sec2"><title>Methods</title><p>U87MG/T98G/U251MG/DBTRG-05MG were subjected to high-throughput sequencing, and obtained data were explored via weighted gene co-expression network analysis, differential expression analysis, functional annotation, and network building. Following the identification of the most relevant DBTRG-distinguishing driver genes, data from GBM patients were employed for, e.g., differential expression analysis, survival analysis, and principal component analysis.</p></sec><sec id="sec3"><title>Results</title><p>Although most driver genes were unique for each cell line, some were inversely regulated in DBTRG-05MG. Alongside driver genes, the differentially-expressed genes were used to build a WWOX-related network depicting protein–protein interactions in U87MG/T98G/U251MG/DBTRG-05MG. This network revealed processes distinctly regulated in DBTRG-05MG, e.g., microglia proliferation or neurofibrillary tangle assembly. <italic>POLE4</italic> and <italic>HSF2BP</italic> were selected as DBTRG-discriminating driver genes based on the gene significance, module membership, and fold-change. Alongside <italic>WWOX</italic>, <italic>POLE4</italic> and <italic>HSF2BP</italic> expression was used to stratify patients into cell lines-resembling groups that differed in, e.g., prognosis and treatment response. Some differences from a WWOX-related network were certified in patients, revealing genes that clarify clinical outcomes. Presumably, <italic>WWOX</italic> overexpression in DBTRG-05MG resulted in expression profile change resembling that of patients with inferior prognosis and drug response. Among these patients, WWOX may be inaccessible for its partners and does not manifest its anti-cancer activity, which was proposed in the literature but not regarding glioblastoma or concerning <italic>POLE4</italic> and <italic>HSF2BP</italic>.</p></sec><sec id="sec4"><title>Conclusion</title><p>Cell lines data enabled the identification of patients among which, despite high expression of <italic>WWOX</italic> tumor suppressor, no advantageous outcomes were noted due to the cancer-promoting profile ensured by other genes.</p></sec>