Injury programs shape glioblastoma

Brooks, Lucy; Ragdale, Holly Simpson; Hill, Ciaran Scott; Clements, Melanie; Parrinello, Simona

doi:10.1016/j.tins.2022.08.006

Cited by 5 publications

(7 citation statements)

References 120 publications

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“…Functional annotation of these genes suggested that patients differ in, e.g., response to axon injury, locomotory behavior, synapse organization, and myeloid cell differentiation ( Supplementary Figure S2 ). Not only the relationship between neurodevelopmental and injury programs has recently emerged as a crucial factor influencing treatment sensitivity, but also the injury responses may act as supplementary drivers of phenotypic heterogeneity ( Brooks et al, 2022 ). Pathways associated with locomotory behavior were highly expressed in high-risk GBM patients ( Wang et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

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

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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IntroductionGlioblastoma (GBM) is notorious for its clinical and molecular heterogeneity, contributing to therapeutic failure and a grim prognosis. WWOX 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 WWOX 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.MethodsU87MG/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.ResultsAlthough 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. POLE4 and HSF2BP were selected as DBTRG-discriminating driver genes based on the gene significance, module membership, and fold-change. Alongside WWOX, POLE4 and HSF2BP 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, WWOX 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 POLE4 and HSF2BP.ConclusionCell lines data enabled the identification of patients among which, despite high expression of WWOX tumor suppressor, no advantageous outcomes were noted due to the cancer-promoting profile ensured by other genes.

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Section: Resultsmentioning

confidence: 99%

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

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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“…Furthermore, adult diffuse gliomas exhibit a higher proportion of AC-Like cells compared to pediatric diffuse gliomas. This distinction could partially account for the more aggressive nature of adult gliomas ( 33 , 43 ). Given these findings, the pronounced expression of BTN3A1 in AC-Like cells supports our initial observations, underscoring BTN3A1’s potential as a promising marker for glioblastomas.…”

Section: Discussionmentioning

confidence: 99%

High expression of BTN3A1 is associated with clinical and immunological characteristics and predicts a poor prognosis in advanced human gliomas

Kone,

Ghouzlani,

Qandouci

et al. 2024

Front. Immunol.

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IntroductionGliomas represent the most prevalent and aggressive tumors within the central nervous system. Despite the current standard treatments, the median survival time for glioblastoma patients remains dismal, hovering around 14 months. While attempts have been made to inhibit the PD-1/PD-L1 and CTLA-4/CD80-CD86 axes through immunotherapy, the outcomes have yet to demonstrate significant efficacy. The immune checkpoint Butyrophilin 3A1 (BTN3A1) can either be involved in advantageous or detrimental function depending on the cancer type.MethodsIn our study, we utilized a Moroccan cohort to delve into the role of BTN3A1 in gliomas. A transcriptomic analysis was conducted on 34 patients, which was then corroborated through a protein analysis in 27 patients and validated using the TCGA database (n = 667).ResultsOur results revealed an elevated expression of BTN3A1 in glioblastoma (grade 4), as evidenced in both the TCGA database and our cohort of Moroccan glioma patients. Within the TCGA cohort, BTN3A1 expression was notably higher in patients with wild-type IDH. We observed a positive correlation between BTN3A1 expression and immune infiltration of B cells, CD8+ T cells, naive CD4+ T cells, and M2 macrophages. Patients exhibiting increased BTN3A1 expression also presented elevated levels of TGF‐β, IL‐10, and TIM‐3 compared to those with reduced BTN3A1 expression. Notably, patients with high BTN3A1 expression were associated with a poorer prognosis than their counterparts with lower expression.ConclussionOur findings suggest that BTN3A1 might promote the establishment of an immunosuppressive microenvironment. Consequently, targeting BTN3A1 could offer novel therapeutic avenues for the management of advanced gliomas.

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“…It is tempting to speculate that the mechanisms identified here may be relevant to glioblastoma recurrence, which in the majority of patients occurs within 2 cm of the resection cavity. 78 , 79 The exposure of residual tumor cells to injury signals induced by surgery, chemotherapy, and radiotherapy in this region 12 , 80 , 81 may convert residual p53-deficient tumor cells to a cancer-initiating, NSC-like state.…”

Section: Discussionmentioning

confidence: 99%

“…This is of relevance to glioma, as injury programs have emerged as major players in disease progression and recurrence, which develops within the inflammatory post-treatment microenvironment. 10 , 11 , 12 In this context, p53 is a particularly interesting candidate as it inhibits somatic cell reprogramming 13 , 14 , 15 and is one of the most commonly inactivated tumor suppressors in glioma. 16 In the adult subventricular zone (SVZ) neurogenic niche, p53 modulates neurogenesis by suppressing the proliferation of transit-amplifying progenitors and their differentiation to neuroblasts.…”

Section: Introductionmentioning

confidence: 99%