bims-cabrim 2022-08-14 papers

Adv Biol (Weinh). 2022 Aug 11. e2200122

Neuron-Glial Interactions in Health and Brain Cancer.

Brain tumors are devastating diseases of the central nervous system. Brain tumor pathogenesis depends on both tumor-intrinsic oncogenic programs and extrinsic microenvironmental factors, including neurons and glial cells. Glial cells (oligodendrocytes, astrocytes, and microglia) make up half of the cells in the brain, and interact with neurons to modulate neurodevelopment and plasticity. Many brain tumor cells exhibit transcriptomic profiles similar to macroglial cells (oligodendrocytes and astrocytes) and their progenitors, making them likely to subvert existing neuron-glial interactions to support tumor pathogenesis. For example, oligodendrocyte precursor cells, a putative glioma cell of origin, can form bona fide synapses with neurons. Such synapses are recently identified in gliomas and drive glioma pathophysiology, underscoring how brain tumor cells can take advantage of neuron-glial interactions to support cancer progression. In this review, it is briefly summarized how neurons and their activity normally interact with glial cells and glial progenitors, and it is discussed how brain tumor cells utilize neuron-glial interactions to support tumor initiation and progression. Unresolved questions on these topics and potential avenues to therapeutically target neuron-glia-cancer interactions in the brain are also pointed out.

Keywords: brain tumor; cancer neuroscience; glioma; neuron-glial interactions; neuron-glioma synapse

DOI: https://doi.org/10.1002/adbi.202200122

Cancer Discov. 2022 Aug 12. OF1

Neuronal Mechanisms Drive Whole Brain Invasion in Glioblastoma.

Whole brain invasion of glioblastoma (GB) is driven by single GB cells with neuronal features.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-146

Cancers (Basel). 2022 Jul 31. pii: 3743. [Epub ahead of print]14(15):

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy.

Andrew M Hersh, Hallie Gaitsch, Safwan Alomari, Daniel Lubelski, Betty M Tyler.

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.

Keywords: glioblastoma; molecular pathway; stem cell; targeted therapy

DOI: https://doi.org/10.3390/cancers14153743

Front Immunol. 2022 ;13 948630

RNA N1-methyladenosine regulator-mediated methylation modification patterns and heterogeneous signatures in glioma.

Meng Mao, Qinjun Chu, Yongli Lou, Peipei Lv, Lin-Jian Wang.

N1-methyladenosine (m1A) is ubiquitous in eukaryotic RNA and regulates mRNA translation. However, little is known about its regulatory role in glioma. Here, we identified 4 m1A modification-related patterns based on m1A regulators in the TCGA (The Cancer Genome Atlas) and CGGA (Chinese Glioma Genome Atlas) cohorts. The differences in survival prognosis between different clusters were striking. In addition, stemness, genomic heterogeneity, tumor microenvironment (TME), and immune cell infiltration were also significantly different between the poor and best prognostic clusters. To reveal the underlying mechanism, differentially expressed genes (DEGs) between the poor and best prognostic clusters were identified, and then were integrated for weighted correlation network analysis (WGCNA). After Univariate Cox-LASSO-Multivariate Cox analyses, DEGs PLEK2 and ABCC3 were screened as the risk-hub genes and were selected to construct an m1A-related signature. Moreover, ABCC3 exacerbated glioma proliferation and was associated with temozolomide (TMZ) resistance. Overall, our study provided new insights into the function and potential therapeutic role of m1A in glioma.

Keywords: TMZ-resistance; glioma; heterogeneity; m1A; stemness; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2022.948630

Cell Death Dis. 2022 Aug 12. 13(8): 702

Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a.

Jan Clusmann, Klaus-Daniel Cortés Franco, David Alejandro Corredor Suárez, Istvan Katona, Maria Girbes Minguez, Nina Boersch, Karolos-Philippos Pissas, Jakob Vanek, Yuemin Tian, Stefan Gründer.

Eliciting regulated cell death, like necroptosis, is a potential cancer treatment. However, pathways eliciting necroptosis are poorly understood. It has been reported that prolonged activation of acid-sensing ion channel 1a (ASIC1a) induces necroptosis in mouse neurons. Glioblastoma stem cells (GSCs) also express functional ASIC1a, but whether prolonged activation of ASIC1a induces necroptosis in GSCs is unknown. Here we used a tumorsphere formation assay to show that slight acidosis (pH 6.6) induces necrotic cell death in a manner that was sensitive to the necroptosis inhibitor Nec-1 and to the ASIC1a antagonist PcTx1. In addition, genetic knockout of ASIC1a rendered GSCs resistant to acid-induced reduction in tumorsphere formation, while the ASIC1 agonist MitTx1 reduced tumorsphere formation also at neutral pH. Finally, a 20 amino acid fragment of the ASIC1 C-terminus, thought to interact with the necroptosis kinase RIPK1, was sufficient to reduce the formation of tumorspheres. Meanwhile, the genetic knockout of MLKL, the executive protein in the necroptosis cascade, did not prevent a reduction in tumor sphere formation, suggesting that ASIC1a induced an alternative cell death pathway. These findings demonstrate that ASIC1a is a death receptor on GSCs that induces cell death during prolonged acidosis. We propose that this pathway shapes the evolution of a tumor in its acidic microenvironment and that pharmacological activation of ASIC1a might be a potential new strategy in tumor therapy.

DOI: https://doi.org/10.1038/s41419-022-05139-3