bims-malgli 2022-01-23 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–01–23
eight papers selected by
Oltea Sampetrean, Keio University

ALDH1A3 Segregated Expression and Nucleus-Associated Proteasomal Degradation Are Common Traits of Glioblastoma Stem Cells.
Necrotic reshaping of the glioma microenvironment drives disease progression.
Drug Resistance in Glioma Cells Induced by a Mesenchymal-Amoeboid Migratory Switch.
STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death.
Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?
Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma.
Analysis of Factors Affecting 5-ALA Fluorescence Intensity in Visualizing Glial Tumor Cells-Literature Review.
Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas.

Biomedicines. 2021 Dec 22. pii: 7. [Epub ahead of print]10(1):

ALDH1A3 Segregated Expression and Nucleus-Associated Proteasomal Degradation Are Common Traits of Glioblastoma Stem Cells.

Julian Fauß, Bettina Sprang, Petra Leukel, Clemens Sommer, Teodora Nikolova, Florian Ringel, Ella L Kim.

  Aldehyde dehydrogenase 1 isoforms A1 and A3 have been implicated as functional biomarkers associated with distinct molecular subtypes of glioblastoma and glioblastoma stem cells. However, the exact roles of these isoforms in different types of glioma cells remain unclear. The purpose of this study was to dissect the association of A1 or A3 isoforms with stem and non-stem glioblastoma cells. This study has undertaken a systematic characterization of A1 and A3 proteins in glioblastoma tissues and a panel of glioblastoma stem cells using immunocytochemical and immunofluorescence staining, Western blot and the subcellular fractionation methodology. Our main findings are (i) human GSCs express uniformly ALDH1A3 but not the ALDH1A1 isoform whereas non-stem glioma cells comparably express both isoforms; (ii) there is an abundance of ALDH1A3 peptides that prevail over the full-length form in glioblastoma stem cells but not in non-stem glioma cells; (iii) full-length ALDH1A3 and ALDH1A3 peptides are spatially segregated within the cell; and (vi) the abundance of full-length ALDH1A3 and ALDH1A3 peptides is sensitive to MG132-mediated proteasomal inhibition. Our study further supports the association of ALDH1A3 with glioblastoma stem cells and provide evidence for the regulation of ALDH1A3 activities at the level of protein turnover.

Keywords:  ALDH1; glioblastoma; glioma stem cells; proteasomal degradation; protein turnover

DOI:  https://doi.org/10.3390/biomedicines10010007
Acta Neuropathol. 2022 Jan 17.

Necrotic reshaping of the glioma microenvironment drives disease progression.

Steven M Markwell, James L Ross, Cheryl L Olson, Daniel J Brat.

  Glioblastoma is the most common primary brain tumor and has a dismal prognosis. The development of central necrosis represents a tipping point in the evolution of these tumors that foreshadows aggressive expansion, swiftly leading to mortality. The onset of necrosis, severe hypoxia and associated radial glioma expansion correlates with dramatic tumor microenvironment (TME) alterations that accelerate tumor growth. In the past, most have concluded that hypoxia and necrosis must arise due to "cancer outgrowing its blood supply" when rapid tumor growth outpaces metabolic supply, leading to diffusion-limited hypoxia. However, growing evidence suggests that microscopic intravascular thrombosis driven by the neoplastic overexpression of pro-coagulants attenuates glioma blood supply (perfusion-limited hypoxia), leading to TME restructuring that includes breakdown of the blood-brain barrier, immunosuppressive immune cell accumulation, microvascular hyperproliferation, glioma stem cell enrichment and tumor cell migration outward. Cumulatively, these adaptations result in rapid tumor expansion, resistance to therapeutic interventions and clinical progression. To inform future translational investigations, the complex interplay among environmental cues and myriad cell types that contribute to this aggressive phenotype requires better understanding. This review focuses on contributions from intratumoral thrombosis, the effects of hypoxia and necrosis, the adaptive and innate immune responses, and the current state of targeted therapeutic interventions.

Keywords:  Glioblastoma; Necrosis; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s00401-021-02401-4
Biomedicines. 2021 Dec 22. pii: 9. [Epub ahead of print]10(1):

Drug Resistance in Glioma Cells Induced by a Mesenchymal-Amoeboid Migratory Switch.

Sophie E Ketchen, Filomena O Gamboa-Esteves, Sean E Lawler, Michal O Nowicki, Arndt Rohwedder, Sabine Knipp, Sally Prior, Susan C Short, John E Ladbury, Anke Brüning-Richardson.

  Cancer cell invasion is a precondition for tumour metastasis and represents one of the most devastating characteristics of cancer. The development of drugs targeting cell migration, known as migrastatics, may improve the treatment of highly invasive tumours such as glioblastoma (GBM). In this study, investigations into the role of the cell adhesion protein Cellular communication network factor 1 (CCN1, also known as CYR61) in GBM cell migration uncovered a drug resistance mechanism adopted by cells when treated with the small molecule inhibitor CCG-1423. This inhibitor binds to importin α/β inhibiting the nuclear translocation of the transcriptional co-activator MKL1, thus preventing downstream effects including migration. Despite this reported role as an inhibitor of cell migration, we found that CCG-1423 treatment did not inhibit GBM cell migration. However, we could observe cells now migrating by mesenchymal-amoeboid transition (MAT). Furthermore, we present evidence that CCN1 plays a critical role in the progression of GBM with increased expression in higher-grade tumours and matched blood samples. These findings support a potential role for CCN1 as a biomarker for the monitoring and potentially early prediction of GBM recurrence, therefore as such could help to improve treatment of and increase survival rates of this devastating disease.

Keywords:  CCN1; biomarker; glioblastoma; invasion; mesenchymal–amoeboid transition; migration

DOI:  https://doi.org/10.3390/biomedicines10010009
Cancers (Basel). 2022 Jan 11. pii: 339. [Epub ahead of print]14(2):

STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death.

Janina Remy, Benedikt Linder, Ulrike Weirauch, Bryan W Day, Brett W Stringer, Christel Herold-Mende, Achim Aigner, Knut Krohn, Donat Kögel.

  Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.

Keywords:  STAT3; autophagy; autophagy-dependent cell death; glioblastoma; lysosomal-dependent cell death; lysosome; pimozide

DOI:  https://doi.org/10.3390/cancers14020339
Cancers (Basel). 2022 Jan 09. pii: 312. [Epub ahead of print]14(2):

Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?

Paulina Zofia Goryńska, Kamila Chmara, Bogumiła Kupcewicz, Krzysztof Goryński, Karol Jaroch, Dariusz Paczkowski, Jacek Furtak, Marek Harat, Barbara Bojko.

  Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies.

Keywords:  1p19q codeletion; IDH; SPME; brain tumor; glioma; metabolomics

DOI:  https://doi.org/10.3390/cancers14020312
Cells. 2022 Jan 13. pii: 263. [Epub ahead of print]11(2):

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma.

Michele Persico, Claudia Abbruzzese, Silvia Matteoni, Paola Matarrese, Anna Maria Campana, Veronica Villani, Andrea Pace, Marco G Paggi.

  Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.

Keywords:  antipsychotic drugs; drug repositioning; drug repurposing; glioblastoma; review

DOI:  https://doi.org/10.3390/cells11020263
Int J Mol Sci. 2022 Jan 15. pii: 926. [Epub ahead of print]23(2):

Analysis of Factors Affecting 5-ALA Fluorescence Intensity in Visualizing Glial Tumor Cells-Literature Review.

Marek Mazurek, Dariusz Szczepanek, Anna Orzyłowska, Radosław Rola.

  Glial tumors are one of the most common lesions of the central nervous system. Despite the implementation of appropriate treatment, the prognosis is not successful. As shown in the literature, maximal tumor resection is a key element in improving therapeutic outcome. One of the methods to achieve it is the use of fluorescent intraoperative navigation with 5-aminolevulinic acid. Unfortunately, often the level of fluorescence emitted is not satisfactory, resulting in difficulties in the course of surgery. This article summarizes currently available knowledge regarding differences in the level of emitted fluorescence. It may depend on both the histological type and the genetic profile of the tumor, which is reflected in the activity and expression of enzymes involved in the intracellular metabolism of fluorescent dyes, such as PBGD, FECH, UROS, and ALAS. The transport of 5-aminolevulinic acid and its metabolites across the blood-brain barrier and cell membranes mediated by transporters, such as ABCB6 and ABCG2, is also important. Accompanying therapies, such as antiepileptic drugs or steroids, also have an impact on light emission by tumor cells. Accurate determination of the factors influencing the fluorescence of 5-aminolevulinic acid-treated cells may contribute to the improvement of fluorescence navigation in patients with highly malignant gliomas.

Keywords:  5-aminolevulinic acid; glioblastoma; high-grade glioma; intraoperative navigation

DOI:  https://doi.org/10.3390/ijms23020926
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab177

Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas.

Wesley S van de Geer, Youri Hoogstrate, Kaspar Draaisma, Pierre A Robe, Sander Bins, Ron H J Mathijssen, Pim French, Harmen J G van de Werken, Filip Y F de Vos.

   Background: The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy, and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve patient survival is urgently needed. Whole-genome sequencing (WGS) is the most comprehensive means to identify such DNA-level targets. We report a unique set of WGS samples along with comprehensive analyses of the glioblastoma genome and potential clinical impact of WGS.
Methods: Our cohort consisted of 42 glioblastoma tumor tissue and matched whole-blood samples, which were whole-genome sequenced as part of the CPCT-02 study. Somatic single-nucleotide variants, small insertions/deletions, multi-nucleotide variants, copy-number alterations (CNAs), and structural variants were analyzed. These aberrations were harnessed to investigate driver genes, enrichments in CNAs, mutational signatures, fusion genes, and potential targeted therapies.
Results: Tumor mutational burden (TMB) was similar to other WGS efforts (1-342 mutations per megabase pair). Mutational analysis in low TMB samples showed that the age-related CpG demethylation signature was dominant, while hyper- and ultramutated tumors had additional defective DNA mismatch repair signatures and showed microsatellite instability in their genomes. We detected chromothripsis in 24% of our cohort, recurrently on chromosomes 1 and 12. Recurrent noncoding regions only resulted in TERT promoter variants. Finally, we found biomarkers and potentially druggable changes in all but one of our tumor samples.
Conclusions: With high-quality WGS data and comprehensive methods, we identified the landscape of driver gene events and druggable targets in glioblastoma patients.

Keywords:  genomics; glioblastoma; precision medicine; whole-genome sequencing

DOI:  https://doi.org/10.1093/noajnl/vdab177