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Glioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12–15 months and just 3–5% of survival over 5 years. This is mainly because most patients suffer recurrence after treatment that currently consists in maximal resection followed by radio- and chemotherapy with temozolomide. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial–mesenchymal transition associated with other aggressive cancers. In this review we frame this process in the high degree of phenotypic inter- and intra-tumor heterogeneity of GBM, which exists in different subtypes, each one characterized by further phenotypic variability in its stem-cell compartment. Under the selective pressure of different treatment agents PMT is induced. The mechanisms involved, as well as the significance of such event in the acquisition of a multitherapy resistance phenotype, are taken in consideration for future perspectives in new anti-GBM therapeutic options.

Background Resistance to temozolomide (TMZ) is a major obstacle to preventing glioblastoma (GBM) recurrence after surgery. Although long noncoding RNAs (lncRNAs) play a variety of roles in GBM, the lncRNAs that regulate TMZ resistance have not yet been clearly elucidated. This study aims to identify lncRNAs that may affect TMZ treatment sensitivity and to explore novel therapeutic strategies to overcome TMZ resistance in GBM. Methods LncRNAs associated with TMZ resistance were identified using the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Quantitative real-time PCR (qRT–PCR) was used to determine the expression of PDIA3P1 in TMZ-resistant and TMZ-sensitive GBM cell lines. Both gain-of-function and loss-of-function studies were used to assess the effects of PDIA3P1 on TMZ resistance using in vitro and in vivo assays. Glioma stem cells (GSCs) were used to determine the effect of PDIA3P1 on the GBM subtype. The hypothesis that PDIA3P1 promotes proneural-to-mesenchymal transition (PMT) was established using bioinformatics analysis and functional experiments. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between PDIA3P1 and C/EBPβ. The posttranslational modification mechanism of C/EBPβ was verified using ubiquitination and coimmunoprecipitation (co-IP) experiments. CompuSyn was leveraged to calculate the combination index (CI), and the antitumor effect of TMZ combined with nefllamapimod (NEF) was validated both in vitro and in vivo. Results We identified a lncRNA, PDIA3P1, which was upregulated in TMZ-resistant GBM cell lines. Overexpression of PDIA3P1 promoted the acquisition of TMZ resistance, whereas knockdown of PDIA3P1 restored TMZ sensitivity. PDIA3P1 was upregulated in MES-GBM, promoted PMT progression in GSCs, and caused GBMs to be more resistant to TMZ treatment. Mechanistically, PDIA3P1 disrupted the C/EBPβ-MDM2 complex and stabilized the C/EBPβ protein by preventing MDM2-mediated ubiquitination. Expression of PDIA3P1 was upregulated in a time- and concentration-dependent manner in response to TMZ treatment, and TMZ-induced upregulation of PDIA3P1 was mediated by the p38α-MAPK signaling pathway. NEF is a small molecule drug that specifically targets p38α with excellent blood–brain barrier (BBB) permeability. NEF blocked TMZ-responsive PDIA3P1 upregulation and produced synergistic effects when combined with TMZ at specific concentrations. The combination of TMZ and NEF exhibited excellent synergistic antitumor effects both in vitro and in vivo. Conclusion PDIA3P1 promotes PMT by stabilizing C/EBPβ, reducing the sensitivity of GBM cells to TMZ treatment. NEF inhibits TMZ-responsive PDIA3P1 upregulation, and NEF combined with TMZ provides better antitumor effects.

[This corrects the article DOI: 10.3389/fnins.2022.919462.].

Notch signaling plays a pivotal role in many cancers, including glioblastoma (GBM). Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) is a key transcription factor of the Notch signaling pathway. Here, we interrogated the function of RBPJ in GBM. Firstly, RBPJ expression of GBM samples was examined. Then, we knocked down RBPJ expression in 2 GBM cell lines (U251 and T98) and 4 glioblastoma (GBM) stem‐like cell lines derived from surgical samples of GBM (KGS01, KGS07, KGS10 and KGS15) to investigate the effect on cell proliferation, invasion, stemness, and tumor formation ability. Expression of possible downstream targets of RBPJ was also assessed. RBPJ was overexpressed in the GBM samples, downregulation of RBPJ reduced cell proliferation and the invasion ability of U251 and T98 cells and cell proliferation ability and stemness of glioblastoma stem‐like cells (GSC) lines. These were accompanied by reduced IL‐6 expression, reduced activation of STAT3, and inhibited proneural‐mesenchymal transition (PMT). Tumor formation and PMT were also impaired by RBPJ knockdown in vivo. In conclusion, RBPJ promotes cell proliferation, invasion, stemness, and tumor initiation ability in GBM cells through enhanced activation of IL‐6‐STAT3 pathway and PMT, inhibition of RBPJ may constitute a prospective treatment for GBM. The expression of recombination signal binding protein for immunoglobulin kappa J region (RBPJ) tended to correlate positively with malignancy of glioma and is highly expressed in glioblastoma stem‐like cells (GSCs). RBPJ in GSCs may relate to not only tumor progression and stemness maintenance through the IL‐6‐STAT3 pathway but also proneural‐mesenchymal transition initiating phenotype shift. RBPJ may be a novel therapeutic target for GSCs.

Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.

Proneural genes play a crucial role in neuronal differentiation. However, our understanding of the regulatory mechanisms governing proneural genes during neuronal differentiation remains limited. RFX4, identified as a candidate regulator of proneural genes, has been reported to be associated with the development of neuropsychiatric disorders. To uncover the regulatory relationship, we utilized a combination of multi-omics data, including ATAC-seq, ChIP-seq, Hi-C, and RNA-seq, to identify RFX4 as an upstream regulator of proneural genes. We further validated the role of RFX4 using an in vitro model of neuronal differentiation with RFX4 knock-in and a CRISPR-Cas9 knock-out system. As a result, we found that RFX4 directly interacts with the promoters of POU3F2 and NEUROD1. Transcriptomic analysis revealed a set of genes associated with neuronal development, which are highly implicated in the development of neuropsychiatric disorders, including schizophrenia. Notably, ectopic expression of RFX4 can drive human embryonic stem cells toward a neuronal fate. Our results strongly indicate that RFX4 serves as a direct upstream regulator of proneural genes, a role that is essential for normal neuronal development. Impairments in RFX4 function could potentially be related to the development of various neuropsychiatric disorders. However, understanding the precise mechanisms by which the RFX4 gene influences the onset of neuropsychiatric disorders requires further investigation through human genetic studies.

Glioblastoma (GBM) resistance to chemoradiotherapy is a major factor contributing to poor treatment outcomes. This resistance markedly affects the effectiveness of surgery combined with chemoradiotherapy and leads to post‐surgical tumor recurrence. Therefore, exploring the mechanisms underlying chemoradiotherapy resistance in GBM is crucial for understanding its progression and improving therapeutic options. This study found that moesin (MSN) acts as a key promotor of chemoradiotherapy resistance in glioma stem cells (GSCs), enhancing their proliferation and stemness maintenance. Mechanistically, MSN activates the downstream PI3K/mTOR signaling pathway, driving the proneural‐to‐mesenchymal transition (PMT) in GSCs. This process enhances the repair of DNA damage caused by radiotherapy (RT) and temozolomide (TMZ), thereby increasing the resistance of GSCs to chemoradiotherapy. Additionally, GNE‐317, a small molecule drug capable of crossing the blood‐brain barrier, specifically inhibits MSN and suppresses the activation of downstream PI3K/mTOR signaling. Importantly, the combination of GNE‐317 with RT and TMZ exhibits a strong synergistic effect both in vivo and in vitro, achieving better efficacy compared to the traditional combination of RT and TMZ. This study not only advances understanding of the mechanisms underlying chemoradiotherapy resistance in GBM but also provides a promising new approach for enhancing treatment outcomes. The study identifies MSN as a key regulator of proneural‐to‐mesenchymal transition (PMT) in GSCs, driving resistance to radiotherapy (RT) and temozolomide (TMZ) in glioblastoma (GBM). However, GNE‐317 specifically inhibits MSN, reverses PMT, resensitizes cells to therapy, and shows promise as a targeted strategy to overcome chemoradiotherapy resistance in GBM.

Diffuse gliomas are primary brain tumors including glioblastomas (GB), astrocytomas, and oligodendrogliomas, the latter two harboring IDH1 mutations and exhibiting slower progression. Gliomas display cellular plasticity, with transitions between astrocyte-like, oligodendrocyte-like, progenitor-like, and mesenchymal-like states driven by genetic alterations and microenvironmental signals. The proneural-to-mesenchymal transition (PMT), associated with increased malignancy, is tightly regulated by the tumor microenvironment, notably through cytokine signaling and non-tumor cell interactions. Endothelins (ET-1, ET-2, ET-3), vasoactive peptides mainly produced by vascular cells, signal through the G-protein-coupled receptors EDNRA and EDNRB and were previously suggested to promote glioma proliferation based on serum-based models. Here, we revisited endothelin signaling using eleven serum-free glioma lines and tumor samples. Multi-omics and electrophysiological analyses identified EDNRB as the predominant receptor, enriched in astrocyte-like cells, increased by BMPs or growth factor withdrawal, and repressed by interferons, IL-6 family cytokines, endothelins, and Hippo/YAP signaling. EDNRA was confined to a perivascular tumor subpopulation and induced by Notch signaling selectively in GB. Functionally, endothelins reduced proliferation while promoting migration and PMT via EDNRB-dependent Ca signaling, ERK/STAT3 activation, and apamin-sensitive SK2/SK3 potassium channel activity. Collectively these findings establish endothelin signaling as an important regulator of glioma cell plasticity and behavior.

Formation of the central nervous system requires a period of extensive progenitor cell proliferation, accompanied or closely followed by differentiation; the balance between these two processes in various regions of the central nervous system gives rise to differential growth and cellular diversity. The correlation between cell cycle lengthening and differentiation has been reported across several types of cell lineage and from diverse model organisms, both in vivo and in vitro. Furthermore, different cell fates might be determined during different phases of the preceding cell cycle, indicating direct cell cycle influences on both early lineage commitment and terminal cell fate decisions. Significant advances have been made in the last decade and have revealed multi-directional interactions between the molecular machinery regulating the processes of cell proliferation and neuronal differentiation. Here, we first introduce the modes of proliferation in neural progenitor cells and summarise evidence linking cell cycle length and neuronal differentiation. Second, we describe the manner in which components of the cell cycle machinery can have additional and, sometimes, cell-cycle-independent roles in directly regulating neurogenesis. Finally, we discuss the way that differentiation factors, such as proneural bHLH proteins, can promote either progenitor maintenance or differentiation according to the cellular environment. These intricate connections contribute to precise coordination and the ultimate division versus differentiation decision.

Glioblastoma multiforme (GBM), whose pathogenesis involves proneural-to-mesenchymal transition (PMT), is the most malignant type of glioma and is associated with a bleak prognosis. Lactate dehydrogenase (LDH) comprises two major subunits, LDHA and LDHB, which can assemble into five different isoenzymes (LDH1-5). However, the role of LDH isoenzyme and its subunits in different GBM subtypes is largely unknown. Our findings reveal that LDHA and LDHB subunits correlated with mesenchymal and proneural subtype classification, and have prognostic and clinical significance in GBM patients. Moreover, it is demonstrated that LDH5, characterized by high LDHA and low LDHB levels, is highly expressed in mesenchymal subtype GBM cells and promotes proliferation, migration, and PMT. Conversely, proneural subtype GBM cells exhibited LDH1 dominance, and low LDHA and high LDHB levels. Notably, LDH1 played a pivotal role in the proliferation, migration, and PMT of proneural glioma cells. For treatment of proneural subtype GBM, gossypol-acetic acid (GAA)-bovine serum albumin (BSA) nanoparticles (GAA-BSA NPs) were developed to ameliorate PMT by targeting LDH1. These nanoparticles effectively suppress proneural subtype tumor growth both and , surpassing their efficacy against the mesenchymal subtype. The results offer several novel insights into the role of LDH isoenzyme in subtype classification between mesenchymal and proneural GBM and provide a promising therapeutic approach for proneural subtype GBM.