bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–09–11
twelve papers selected by
Oltea Sampetrean, Keio University
  1. AQP4-dependent glioma cell features affect the phenotype of surrounding cells via extracellular vesicles.
  2. Magnetic resonance spectroscopy outperforms perfusion in distinguishing between pseudoprogression and disease progression in patients with glioblastoma.
  3. Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression.
  4. CPEB2 m6A methylation regulates blood-tumor barrier permeability by regulating splicing factor SRSF5 stability.
  5. Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs.
  6. Metabolic management of microenvironment acidity in glioblastoma.
  7. A RUNX-targeted gene switch-off approach modulates the BIRC5/PIF1-p21 pathway and reduces glioblastoma growth in mice.
  8. Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.
  9. VRK1 is a Synthetic Lethal Target in VRK2-deficient Glioblastoma.
  10. Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma.
  11. Integrative and comparative single-cell analysis reveals transcriptomic difference between human tumefactive demyelinating lesion and glioma.
  12. Aerobic Glycolysis Promotes an NF-κB-Mediated Increase in PD-L1 Expression.
  1. Cell Biosci. 2022 Sep 07. 12(1): 150
    AQP4-dependent glioma cell features affect the phenotype of surrounding cells via extracellular vesicles.
    Laura Simone, Francesco Pisani, Elena Binda, Antonio Frigeri, Angelo L Vescovi, Maria Svelto, Grazia P Nicchia.
       BACKGROUND: Extracellular vesicles (EVs) are membrane-enclosed particles released systemically by all cells, including tumours. Tumour EVs have been shown to manipulate their local environments as well as distal targets to sustain the tumour in a variety of tumours, including glioblastoma (GBM). We have previously demonstrated the dual role of the glial water channel aquaporin-4 (AQP4) protein in glioma progression or suppression depending on its aggregation state. However, its possible role in communication mechanisms in the microenvironment of malignant gliomas remains to be unveiled.
    RESULTS: Here we show that in GBM cells AQP4 is released via EVs that are able to affect the GBM microenvironment. To explore this role, EVs derived from invasive GBM cells expressing AQP4-tetramers or apoptotic GBM cells expressing orthogonal arrays of particles (AQP4-OAPs) were isolated, using a differential ultracentrifugation method, and were added to pre-seeded GBM cells. Confocal microscopy analysis was used to visualize the interaction and uptake of AQP4-containing EVs by recipient cells. Chemoinvasion and Caspase3/7 activation assay, performed on recipient cells after EVs uptake, revealed that EVs produced by AQP4-tetramers expressing cells were able to drive surrounding tumour cells toward the migratory phenotype, whereas EVs produced by AQP4-OAPs expressing cells drive them toward the apoptosis pathway.
    CONCLUSION: This study demonstrates that the different GBM cell phenotypes can be transferred by AQP4-containing EVs able to influence tumour cell fate toward invasiveness or apoptosis. This study opens a new perspective on the role of AQP4 in the brain tumour microenvironment associated with the EV-dependent communication mechanism.
    Keywords:  AQP4; Apoptosis; EVs; GBM; Migration; Tumour environment
    DOI:  https://doi.org/10.1186/s13578-022-00888-2
  2. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac128
    Magnetic resonance spectroscopy outperforms perfusion in distinguishing between pseudoprogression and disease progression in patients with glioblastoma.
    Mohamed E El-Abtah, Pratik Talati, Melanie Fu, Benjamin Chun, Patrick Clark, Anna Peters, Anthony Ranasinghe, Julian He, Otto Rapalino, Tracy T Batchelor, R Gilberto Gonzalez, William T Curry, Jorg Dietrich, Elizabeth R Gerstner, Eva-Maria Ratai.
       Background: There is a need to establish biomarkers that distinguish between pseudoprogression (PsP) and true tumor progression in patients with glioblastoma (GBM) treated with chemoradiation.
    Methods: We analyzed magnetic resonance spectroscopic imaging (MRSI) and dynamic susceptibility contrast (DSC) MR perfusion data in patients with GBM with PsP or disease progression after chemoradiation. MRSI metabolites of interest included intratumoral choline (Cho), myo-inositol (mI), glutamate + glutamine (Glx), lactate (Lac), and creatine on the contralateral hemisphere (c-Cr). Student T-tests and area under the ROC curve analyses were used to detect group differences in metabolic ratios and their ability to predict clinical status, respectively.
    Results: 28 subjects (63 ± 9 years, 19 men) were evaluated. Subjects with true progression (n = 20) had decreased enhancing region mI/c-Cr (P = .011), a marker for more aggressive tumors, compared to those with PsP, which predicted tumor progression (AUC: 0.84 [0.76, 0.92]). Those with true progression had elevated Lac/Glx (P = .0009), a proxy of the Warburg effect, compared to those with PsP which predicted tumor progression (AUC: 0.84 [0.75, 0.92]). Cho/c-Cr did not distinguish between PsP and true tumor progression. Despite rCBV (AUC: 0.70 [0.60, 0.80]) and rCBF (AUC: 0.75 [0.65, 0.84]) being individually predictive of tumor response, they added no additional predictive value when combined with MRSI metabolic markers.
    Conclusions: Incorporating enhancing lesion MRSI measures of mI/c-Cr and Lac/Glx into brain tumor imaging protocols can distinguish between PsP and true progression and inform patient management decisions.
    Keywords:  glioblastoma (GBM); lactate (Lac); magnetic resonance spectroscopic imaging (MRSI); myo-inositol (mI); pseudoprogression (PsP)
    DOI:  https://doi.org/10.1093/noajnl/vdac128
  3. Oncogene. 2022 Sep 09.
    Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression.
    Ming Li, Hao Xu, Yanhua Qi, Ziwen Pan, Boyan Li, Zijie Gao, Rongrong Zhao, Hao Xue, Gang Li.
      Exosomes can selectively secrete harmful metabolic substances from cells to maintain cellular homeostasis, and complex crosstalk occurs between exosomes and tumor-associated macrophages (TAMs) in the glioma immune microenvironment. However, the precise mechanisms by which these exosome-encapsulated cargos create an immunosuppressive microenvironment remain unclear. Herein, we investigated the effect of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We performed sequencing analysis of cerebrospinal fluid (CSF) and tumor tissues from glioma patients to identify functional microRNAs (miRNAs). High levels of miR-3591-3p were found in CSF and GDEs but not in normal brain tissue or glial cells. Functionally, GDEs and miR-3591-3p significantly induced M2 macrophage polarization and increased the secretion of IL10 and TGFβ1, which in turn promoted glioma invasion and migration. Moreover, miR-3591-3p overexpression in glioma cell lines resulted in G2/M arrest and markedly increased apoptosis. Mechanistically, miR-3591-3p can directly target CBLB and MAPK1 in macrophages and glioma cells, respectively, and further activate the JAK2/PI3K/AKT/mTOR, JAK2/STAT3, and MAPK signaling pathways. In vivo experiments confirmed that macrophages lentivirally transduced with miR-3591-3p can significantly promote glioma progression. Thus, our study demonstrates that tumor-suppressive miR-3591-3p in glioma cells can be secreted via exosomes and target TAMs to induce the formation of an immunosuppressive microenvironment. Collectively, these findings provide new insights into the role of glioma exosomal miRNAs in mediating the establishment of an immunosuppressive tumor microenvironment and show that miR-3591-3p may be a valuable biomarker and that blocking the encapsulation of miR-3591-3p into exosomes may become a novel immunotherapeutic strategy for glioma.
    DOI:  https://doi.org/10.1038/s41388-022-02457-w
  4. Commun Biol. 2022 Sep 05. 5(1): 908
    CPEB2 m6A methylation regulates blood-tumor barrier permeability by regulating splicing factor SRSF5 stability.
    Mengyang Zhang, Chunqing Yang, Xuelei Ruan, Xiaobai Liu, Di Wang, Libo Liu, Lianqi Shao, Ping Wang, Weiwei Dong, Yixue Xue.
      The blood-tumor barrier (BTB) contributes to poor therapeutic efficacy by limiting drug uptake; therefore, elevating BTB permeability is essential for glioma treatment. Here, we prepared astrocyte microvascular endothelial cells (ECs) and glioma microvascular ECs (GECs) as in vitro blood-brain barrier (BBB) and BTB models. Upregulation of METTL3 and IGF2BP3 in GECs increased the stability of CPEB2 mRNA through its m6A methylation. CPEB2 bound to and increased SRSF5 mRNA stability, which promoted the ETS1 exon inclusion. P51-ETS1 promoted the expression of ZO-1, occludin, and claudin-5 transcriptionally, thus regulating BTB permeability. Subsequent in vivo knockdown of these molecules in glioblastoma xenograft mice elevated BTB permeability, promoted doxorubicin penetration, and improved glioma-specific chemotherapeutic effects. These results provide a theoretical and experimental basis for epigenetic regulation of the BTB, as well as insight into comprehensive glioma treatment.
    DOI:  https://doi.org/10.1038/s42003-022-03878-9
  5. CNS Neurosci Ther. 2022 Sep 06.
    Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs.
    Zongqi Wang, Gang Chen.
      Glioma is characterized as the most aggressive brain tumor that occurred in the central nervous system. The circadian rhythm is an essential cyclic change system generated by the endogenous circadian clock. Current studies found that the circadian clock affects glioma pathophysiology. It is still controversial whether the circadian rhythm disruption is a cause or an effect of tumorigenesis. This review discussed the association between cell cycle and circadian clock and provided a prominent molecular theoretical basis for tumor therapy. We illustrated the external factors affecting the circadian clock including thermodynamics, hypoxia, post-translation, and microRNA, while the internal characteristics concerning the circadian clock in glioma involve stemness, metabolism, radiotherapy sensitivity, and chemotherapy sensitivity. We also summarized the molecular pathways and the therapeutic drugs involved in the glioma circadian rhythm. There are still many questions in this field waiting for further investigation. The results of glioma chronotherapy in sensitizing radiation therapy and chemotherapy have shown great therapeutic potential in improving clinical outcomes. These findings will help us further understand the characteristics of glioma pathophysiology.
    Keywords:  cell cycle; circadian clock; glioma; molecular pathway; therapeutic drug
    DOI:  https://doi.org/10.1111/cns.13966
  6. Front Oncol. 2022 ;12 968351
    Metabolic management of microenvironment acidity in glioblastoma.
    Thomas N Seyfried, Gabriel Arismendi-Morillo, Giulio Zuccoli, Derek C Lee, Tomas Duraj, Ahmed M Elsakka, Joseph C Maroon, Purna Mukherjee, Linh Ta, Laura Shelton, Dominic D'Agostino, Michael Kiebish, Christos Chinopoulos.
      Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.
    Keywords:  fermentation; glutamate; glutaminolysis; glycolysis; ketogenic diet; ketogenic metabolic therapy; lactate; succinate
    DOI:  https://doi.org/10.3389/fonc.2022.968351
  7. Commun Biol. 2022 Sep 09. 5(1): 939
    A RUNX-targeted gene switch-off approach modulates the BIRC5/PIF1-p21 pathway and reduces glioblastoma growth in mice.
    Etsuko Yamamoto Hattori, Tatsuya Masuda, Yohei Mineharu, Masamitsu Mikami, Yukinori Terada, Yasuzumi Matsui, Hirohito Kubota, Hidemasa Matsuo, Masahiro Hirata, Tatsuki R Kataoka, Tatsutoshi Nakahata, Shuji Ikeda, Susumu Miyamoto, Hiroshi Sugiyama, Yoshiki Arakawa, Yasuhiko Kamikubo.
      Glioblastoma is the most common adult brain tumour, representing a high degree of malignancy. Transcription factors such as RUNX1 are believed to be involved in the malignancy of glioblastoma. RUNX1 functions as an oncogene or tumour suppressor gene with diverse target genes. Details of the effects of RUNX1 on the acquisition of malignancy in glioblastoma remain unclear. Here, we show that RUNX1 downregulates p21 by enhancing expressions of BIRC5 and PIF1, conferring anti-apoptotic properties on glioblastoma. A gene switch-off therapy using alkylating agent-conjugated pyrrole-imidazole polyamides, designed to fit the RUNX1 DNA groove, decreased expression levels of BIRC5 and PIF1 and induced apoptosis and cell cycle arrest via p21. The RUNX1-BIRC5/PIF1-p21 pathway appears to reflect refractory characteristics of glioblastoma and thus holds promise as a therapeutic target. RUNX gene switch-off therapy may represent a novel treatment for glioblastoma.
    DOI:  https://doi.org/10.1038/s42003-022-03917-5
  8. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac130
    Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.
    Kendra A Porath, Michael S Regan, Jessica I Griffith, Sonia Jain, Sylwia A Stopka, Danielle M Burgenske, Katrina K Bakken, Brett L Carlson, Paul A Decker, Rachael A Vaubel, Sonja Dragojevic, Ann C Mladek, Margaret A Connors, Zeng Hu, Lihong He, Gaspar J Kitange, Shiv K Gupta, Thomas M Feldsien, Didier R Lefebvre, Nathalie Y R Agar, Jeanette E Eckel-Passow, Edward B Reilly, William F Elmquist, Jann N Sarkaria.
       Background: EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood-brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We studied whether convection-enhanced delivery (CED) can be used to safely infuse ADCs into orthotopic patient-derived xenograft (PDX) models of EGFRvIII mutant GBM.
    Methods: The efficacy of the EGFR-targeted ADCs depatuxizumab mafodotin (Depatux-M) and Serclutamab talirine (Ser-T) was evaluated in vitro and in vivo. CED was performed in nontumor and tumor-bearing mice. Immunostaining was used to evaluate ADC distribution, pharmacodynamic effects, and normal cell toxicity.
    Results: Dose-finding studies in orthotopic GBM6 identified single infusion of 2 μg Ser-T and 60 μg Depatux-M as safe and effective associated with extended survival prolongation (>300 days and 95 days, respectively). However, with serial infusions every 21 days, four Ser-T doses controlled tumor growth but was associated with lethal toxicity approximately 7 days after the final infusion. Limiting dosing to two infusions in GBM108 provided profound median survival extension of over 200 days. In contrast, four Depatux-M CED doses were well tolerated and significantly extended survival in both GBM6 (158 days) and GBM108 (310 days). In a toxicity analysis, Ser-T resulted in a profound loss in NeuN+ cells and markedly elevated GFAP staining, while Depatux-M was associated only with modest elevation in GFAP staining.
    Conclusion: CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.
    Keywords:  Depatux-M; Serclutamab talirine; antibody-drug conjugate; convection-enhanced delivery; glioblastoma
    DOI:  https://doi.org/10.1093/noajnl/vdac130
  9. Cancer Res. 2022 Sep 07. pii: CAN-21-4443. [Epub ahead of print]
    VRK1 is a Synthetic Lethal Target in VRK2-deficient Glioblastoma.
    Julie A Shields, Samuel R Meier, Madhavi Bandi, Erin E Mulkearns-Hubert, Nicole Hajdari, Maria Dam Ferdinez, Justin L Engel, Daniel J Silver, Binzhang Shen, Wenhai Zhang, Christopher G Hubert, Kelly Mitchell, Sajina Shakya, Shan-Chuan Zhao, Alborz Bejnood, Minjie Zhang, Robert Tjin Tham Sjin, Erik Wilker, Justin D Lathia, Jannik N Andersen, Yingnan Chen, Fang Li, Barbara Weber, Alan Huang, Natasha Emmanuel.
      Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic lethal interactions by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of vaccinia-related kinase 2 (VRK2), which is silenced by promoter methylation in approximately two-thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-4443
  10. Acta Neuropathol. 2022 Sep 07.
    Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma.
    Robert Siddaway, Laura Canty, Sanja Pajovic, Scott Milos, Etienne Coyaud, Stefanie-Grace Sbergio, Arun Kumaran Vadivel Anguraj, Evan Lubanszky, Hwa Young Yun, Alessia Portante, Sheyenne Carette, Cunjie Zhang, Michael F Moran, Brian Raught, Eric I Campos, Cynthia Hawkins.
      Histone H3 mutations at amino acids 27 (H3K27M) and 34 (H3G34R) are recurrent drivers of pediatric-type high-grade glioma (pHGG). H3K27M mutations lead to global disruption of H3K27me3 through dominant negative PRC2 inhibition, while H3G34R mutations lead to local losses of H3K36me3 through inhibition of SETD2. However, their broader oncogenic mechanisms remain unclear. We characterized the H3.1K27M, H3.3K27M and H3.3G34R interactomes, finding that H3K27M is associated with epigenetic and transcription factor changes; in contrast H3G34R removes a break on cryptic transcription, limits DNA methyltransferase access, and alters mitochondrial metabolism. All 3 mutants had altered interactions with DNA repair proteins and H3K9 methyltransferases. H3K9me3 was reduced in H3K27M-containing nucleosomes, and cis-H3K9 methylation was required for H3K27M to exert its effect on global H3K27me3. H3K9 methyltransferase inhibition was lethal to H3.1K27M, H3.3K27M and H3.3G34R pHGG cells, underscoring the importance of H3K9 methylation for oncohistone-mutant gliomas and suggesting it as an attractive therapeutic target.
    Keywords:  H3G34R; H3K27M; H3K9 methylation; pHGG
    DOI:  https://doi.org/10.1007/s00401-022-02489-2
  11. Commun Biol. 2022 Sep 09. 5(1): 941
    Integrative and comparative single-cell analysis reveals transcriptomic difference between human tumefactive demyelinating lesion and glioma.
    Xiao-Yong Chen, Yue Chen, Wen-Hua Fang, Zan-Yi Wu, Deng-Liang Wang, Ya-Wen Xu, Liang-Hong Yu, Yuan-Xiang Lin, De-Zhi Kang, Chen-Yu Ding.
      Tumefactive demyelinating lesion (TDL) is an immune-mediated disease which can be misdiagnosed as glioma. At present, there is no study comparing difference between the two disorders at the cellular level. Here, we perform integrative and comparative single-cell RNA sequencing (ScRNA-seq) transcriptomic analysis on TDL and glioma lesions. At single-cell resolution, TDL is comprised primarily of immune cells, which is completely different from glioma. The integrated analysis reveals a TDL-specific microglial subset involving in B cell activation and proliferation. Comparative analysis highlights remyelination function of glial cells and demyelination function of T cells in TDL. Subclustering and pseudotime trajectory analysis of T cells in TDL reveal their heterogeneity and diverse functions involving in TDL pathogenesis and recovery process. Our study identifies substantial differences between TDL and glioma at single-cell resolution. The observed heterogeneity and potentially diverse functions of cells in TDL may be critical in disease progression.
    DOI:  https://doi.org/10.1038/s42003-022-03900-0
  12. Cancer Discov. 2022 Sep 09. OF1
    Aerobic Glycolysis Promotes an NF-κB-Mediated Increase in PD-L1 Expression.
      High glucose in the GBM tumor microenvironment promotes immune evasion by increasing PD-L1 expression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-0164
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