bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–09–18
ten papers selected by
Oltea Sampetrean, Keio University
  1. Modulating glioblastoma chemotherapy response: Evaluating long non-coding RNA effects on DNA damage response, glioma stem cell function, and hypoxic processes.
  2. MEX3A impairs DNA mismatch repair signaling and mediates acquired temozolomide resistance in glioblastoma.
  3. Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity.
  4. Maintaining Human Glioblastoma Cellular Diversity Ex vivo using Three-Dimensional Organoid Culture.
  5. Pericyte mediates the infiltration, migration, and polarization of macrophages by CD163/MCAM axis in glioblastoma.
  6. Differential expression of checkpoint markers in the normoxic and hypoxic microenvironment of glioblastomas.
  7. SerpinB3 drives cancer stem cell survival in glioblastoma.
  8. Injury programs shape glioblastoma.
  9. New perspectives in liquid biopsy for glioma patients.
  10. Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.
  1. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac119
    Modulating glioblastoma chemotherapy response: Evaluating long non-coding RNA effects on DNA damage response, glioma stem cell function, and hypoxic processes.
    Edith Yuan, Kristie Liu, Justin Lee, Kathleen Tsung, Frances Chow, Frank J Attenello.
      Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor, with an estimated annual incidence of 17 000 new cases in the United States. Current treatments for GBM include chemotherapy, surgical resection, radiation therapy, and antiangiogenic therapy. However, despite the various therapeutic options, the 5-year survival rate remains at a dismal 5%. Temozolomide (TMZ) is the first-line chemotherapy drug for GBM; however, poor TMZ response is one of the main contributors to the dismal prognosis. Long non-coding RNAs (lncRNAs) are nonprotein coding transcripts greater than 200 nucleotides that have been implicated to mediate various GBM pathologies, including chemoresistance. In this review, we aim to frame the TMZ response in GBM via exploration of the lncRNAs mediating three major mechanisms of TMZ resistance: (1) regulation of the DNA damage response, (2) maintenance of glioma stem cell identity, and (3) exploitation of hypoxia-associated responses.
    Keywords:  Temozolomide; chemo-response; glioblastoma; long non-coding RNAs
    DOI:  https://doi.org/10.1093/noajnl/vdac119
  2. Cancer Res. 2022 Sep 16. pii: CAN-22-2036. [Epub ahead of print]
    MEX3A impairs DNA mismatch repair signaling and mediates acquired temozolomide resistance in glioblastoma.
    Tian Gan, Yan Wang, Manyi Xie, Qiang Wang, Saisai Zhao, Peng Wang, Qinyu Shi, Xuanchen Qian, Faan Miao, Zhigang Shen, Er Nie.
      MutS protein homolog 2 (MSH2) is a key element involved in the DNA mismatch repair system, which is responsible for recognizing and repairing mispaired bases. Simultaneously, MSH2 identifies DNA adducts induced by temozolomide (TMZ) and triggers apoptosis and autophagy in tumor cells. Previous work has revealed that reduced MSH2 expression is often observed in glioblastoma (GBM) patients who relapse after chemotherapy. Elucidation of the mechanism behind TMZ-mediated reduction of MSH2 could help improve GBM treatment. Here, we report significant upregulation of Mex-3 RNA binding family member A (MEX3A) in GBM tissues and cell lines following TMZ treatment. MEX3A bound to the MEX-3 recognition element (MRE) of MSH2 mRNA, which in turn recruited CCR4-NOT complexes to target MSH2 mRNA for deadenylation and degradation. In addition, ectopic expression of MEX3A significantly decreased cellular DNA mismatch repair activities and reduced the chemosensitivity of GBM cells via downregulation of MSH2, while depletion of MEX3A sensitized GBM cells to TMZ. In MGMT-deficient GBM patients, MEX3A expression correlated with MSH2 levels, and high MEX3A expression was associated with poor prognosis. Overall, these findings reveal a potential mechanism by which MSH2 expression is reduced in post-TMZ recurrent GBM.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2036
  3. Cancer Cell. 2022 Sep 01. pii: S1535-6108(22)00378-6. [Epub ahead of print]
    Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity.
    Agnieszka Chryplewicz, Julie Scotton, Mélanie Tichet, Anoek Zomer, Ksenya Shchors, Johanna A Joyce, Krisztian Homicsko, Douglas Hanahan.
      Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.
    Keywords:  VEGF inhibitors; anti-PD-L1 immune checkpoint blockade; glioblastoma immunotherapy; high endothelial venules; histamine receptor signaling; immunostimulatory autophagy; multi-targeted cancer therapy; remodeling tumor vasculature; reprogramming immunosuppressive macrophages; repurposing tricyclic antidepressants
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.014
  4. J Vis Exp. 2022 Aug 25.
    Maintaining Human Glioblastoma Cellular Diversity Ex vivo using Three-Dimensional Organoid Culture.
    Swetha J Sundar, Sajina Shakya, Violette Recinos, Christopher G Hubert.
      Glioblastoma (GBM) is the most commonly occurring primary malignant brain cancer with an extremely poor prognosis. Intra-tumoral cellular and molecular diversity, as well as complex interactions between tumor microenvironments, can make finding effective treatments a challenge. Traditional adherent or sphere culture methods can mask such complexities, whereas three-dimensional organoid culture can recapitulate regional microenvironmental gradients. Organoids are a method of three-dimensional GBM culture that better mimics patient tumor architecture, contains phenotypically diverse cell populations, and can be used for medium-throughput experiments. Although three-dimensional organoid culture is more laborious and time-consuming compared to traditional culture, it offers unique benefits and can serve to bridge the gap between current in vitro and in vivo systems. Organoids have established themselves as invaluable tools in the arsenal of cancer biologists to better understand tumor behavior and mechanisms of resistance, and their applications only continue to grow. Here, details are provided about methods for generating and maintaining GBM organoids. Instructions of how to perform organoid sample embedding and sectioning using both frozen and paraffin-embedding techniques, as well as recommendations for immunohistochemistry and immunofluorescence protocols on organoid sections, and measurement of total organoid cell viability, are all also described.
    DOI:  https://doi.org/10.3791/63745
  5. iScience. 2022 Sep 16. 25(9): 104918
    Pericyte mediates the infiltration, migration, and polarization of macrophages by CD163/MCAM axis in glioblastoma.
    Hao Zhang, Nan Zhang, Wantao Wu, Zeyu Wang, Ziyu Dai, Xisong Liang, Liyang Zhang, Yun Peng, Peng Luo, Jian Zhang, Zaoqu Liu, Quan Cheng, Zhixiong Liu.
      Microenvironment cells (MCs) play a critical role in tumor proliferation, progression, and metastasis. However, it has not been adequately addressed whether MCs could be used as a reliable prognostic marker in glioblastoma (GBM). In the current study, the cell pair (CP) score was constructed in 1137 GBM samples based on the cell pair algorithm and Gaussian finite mixture model (GMM) and was verified in 73 GBM samples from the Xiangya cohort. CP score predicted GBM patients' survival and response to anti-PD-1 treatment with high sensitivity. Macrophage markers CD68 and CD163 were co-expressed with pericyte markers MCAM and MG2. Pericyte could mediate the infiltration, migration, and M2 type polarization of macrophages by MCAM. The CP score was a valuable tool for predicting survival outcomes and guiding immunotherapy for GBM patients. Cell pair pericyte/macrophage and gene pair CD163/MCAM were biologically significant in the tumor microenvironment of GBM.
    Keywords:  Biocomputational method; Cancer; Genomic analysis; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2022.104918
  6. Brain Pathol. 2022 Sep 12. e13111
    Differential expression of checkpoint markers in the normoxic and hypoxic microenvironment of glioblastomas.
    Stine Asferg Petterson, Mia Dahl Sørensen, Mark Burton, Mads Thomassen, Torben A Kruse, Signe Regner Michaelsen, Bjarne Winther Kristensen.
      Glioblastoma is the most common primary malignant brain tumor in adults with an overall survival of only 14.6 months. Hypoxia is known to play a role in tumor aggressiveness but the influence of hypoxia on the immune microenvironment is not fully understood. The aim of this study was to investigate the expression of immune-related proteins in normoxic and hypoxic tumor areas by digital spatial profiling. Tissue samples from 10 glioblastomas were stained with a panel of 40 antibodies conjugated to photo-cleavable oligonucleotides. The free oligo-tags from normoxic and hypoxic areas were hybridized to barcodes for digital counting. Differential expression patterns were validated by Ivy Glioblastoma Atlas Project (GAP) data and an independent patient cohort. We found that CD44, Beta-catenin and B7-H3 were upregulated in hypoxia, whereas VISTA, CD56, KI-67, CD68 and CD11c were downregulated. PD-L1 and PD-1 were not affected by hypoxia. Focusing on the checkpoint-related markers CD44, B7-H3 and VISTA, our findings for CD44 and VISTA could be confirmed with Ivy GAP RNA sequencing data. Immunohistochemical staining and digital quantification of CD44, B7-H3 and VISTA in an independent cohort confirmed our findings for all three markers. Additional stainings revealed fewer T cells and high but equal amounts of tumor-associated microglia and macrophages in both hypoxic and normoxic regions. In conclusion, we found that CD44 and B7-H3 were upregulated in areas with hypoxia whereas VISTA was downregulated together with the presence of fewer T cells. This heterogeneous expression should be taken into consideration when developing novel therapeutic strategies.
    Keywords:  digital spatial profiling; glioblastoma; hypoxia; immune checkpoints
    DOI:  https://doi.org/10.1111/bpa.13111
  7. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01176-7. [Epub ahead of print]40(11): 111348
    SerpinB3 drives cancer stem cell survival in glioblastoma.
    Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen McCortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia.
      Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs.
    Keywords:  CP: Cancer; SerpinB3; cancer stem cell; cathepsin L; glioblastoma; lysosomal-mediated cell death
    DOI:  https://doi.org/10.1016/j.celrep.2022.111348
  8. Trends Neurosci. 2022 Sep 08. pii: S0166-2236(22)00163-1. [Epub ahead of print]
    Injury programs shape glioblastoma.
    Lucy J Brooks, Holly Simpson Ragdale, Ciaran Scott Hill, Melanie Clements, Simona Parrinello.
      Glioblastoma is the most common and aggressive primary brain cancer in adults and is almost universally fatal due to its stark therapeutic resistance. During the past decade, although survival has not substantially improved, major advances have been made in our understanding of the underlying biology. It has become clear that these devastating tumors recapitulate features of neurodevelopmental hierarchies which are influenced by the microenvironment. Emerging evidence also highlights a prominent role for injury responses in steering cellular phenotypes and contributing to tumor heterogeneity. This review highlights how the interplay between injury and neurodevelopmental programs impacts on tumor growth, invasion, and treatment resistance, and discusses potential therapeutic considerations in view of these findings.
    Keywords:  brain tumor; cell type-specific; differentiation; inflammation; microenvironment; treatment resistance
    DOI:  https://doi.org/10.1016/j.tins.2022.08.006
  9. Curr Opin Oncol. 2022 Sep 13.
    New perspectives in liquid biopsy for glioma patients.
    Francesco Pasqualetti, Milena Rizzo, Sara Franceschi, Francesca Lessi, Fabiola Paiar, Francesca M Buffa.
       PURPOSE OF REVIEW: Gliomas are the most common primary tumors of the central nervous system. They are characterized by a disappointing prognosis and ineffective therapy that has shown no substantial improvements in the past 20 years. The lack of progress in treating gliomas is linked with the inadequacy of suitable tumor samples to plan translational studies and support laboratory developments. To overcome the use of tumor tissue, this commentary review aims to highlight the potential for the clinical application of liquid biopsy (intended as the study of circulating biomarkers in the blood), focusing on circulating tumor cells, circulating DNA and circulating noncoding RNA.
    RECENT FINDINGS: Thanks to the increasing sensitivity of sequencing techniques, it is now possible to analyze circulating nucleic acids and tumor cells (liquid biopsy).
    SUMMARY: Although studies on the use of liquid biopsy are still at an early stage, the potential clinical applications of liquid biopsy in the study of primary brain cancer are many and have the potential to revolutionize the approach to neuro-oncology, and importantly, they offer the possibility of gathering information on the disease at any time during its history.
    DOI:  https://doi.org/10.1097/CCO.0000000000000902
  10. Med (N Y). 2022 Sep 08. pii: S2666-6340(22)00365-8. [Epub ahead of print]
    Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.
    Jasmin Sponagel, Jill K Jones, Cheryl Frankfater, Shanshan Zhang, Olivia Tung, Kevin Cho, Kelsey L Tinkum, Hannah Gass, Elena Nunez, Douglas R Spitz, Prakash Chinnaiyan, Jacob Schaefer, Gary J Patti, Maya S Graham, Audrey Mauguen, Milan Grkovski, Mark P Dunphy, Simone Krebs, Jingqin Luo, Joshua B Rubin, Joseph E Ippolito.
       BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue.
    METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity.
    FINDINGS: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition.
    CONCLUSION: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research.
    FUNDING: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund.
    Keywords:  TCA cycle; Translation to patients; cancer metabolism; glioma; glutaminase; glutamine metabolism; glutathione; pyruvate carboxylase; sex differences; solid-state NMR; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.medj.2022.08.005
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