bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–07–31
eight papers selected by
Oltea Sampetrean, Keio University
  1. TRAF4 maintains deubiquitination of Caveolin-1 to drive glioblastoma stemness and Temozolomide resistance.
  2. Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib.
  3. Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity.
  4. Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion.
  5. Butterfly glioblastoma: Clinical characteristics, treatment strategies and outcomes in a population-based cohort.
  6. Integrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis.
  7. Mechanism-based design of agents that selectively target drug-resistant glioma.
  8. The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models.
  1. Cancer Res. 2022 Jul 27. pii: CAN-21-3882. [Epub ahead of print]
    TRAF4 maintains deubiquitination of Caveolin-1 to drive glioblastoma stemness and Temozolomide resistance.
    Yongxu Li, Tiepeng Wang, Quan Wan, Qing Wang, Zhenzhong Chen, Yuan Gao, Yuchen Ye, Jiusheng Lin, Bihuan Zhao, Huaile Wang, Jinming Yang, Kai Zhao, Na Lu.
      Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and Temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified Risperidone interaction with TRAF4, and Risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacological inhibition of TRAF4 with Risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3882
  2. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac095
    Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib.
    Yeshavanth Kumar Banasavadi-Siddegowda, Sriya Namagiri, Yoshihiro Otani, Hannah Sur, Sarah Rivas, Jean-Paul Bryant, Allison Shellbourn, Mitchell Rock, Ashis Chowdhury, Cole T Lewis, Toshihiko Shimizu, Stuart Walbridge, Sivarajan Kumarasamy, Ashish H Shah, Tae Jin Lee, Dragan Maric, Yuanqing Yan, Ji Young Yoo, Sangamesh G Kumbar, John D Heiss, Balveen Kaur.
       Background: The prognosis of glioblastoma (GBM) remains dismal because therapeutic approaches have limited effectiveness. A new targeted treatment using MEK inhibitors, including trametinib, has been proposed to improve GBM therapy. Trametinib had a promising preclinical effect against several cancers, but its adaptive treatment resistance precluded its clinical translation in GBM. Previously, we have demonstrated that protein arginine methyltransferase 5 (PRMT5) is upregulated in GBM and its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. We tested whether inhibition of PRMT5 can enhance the efficacy of trametinib against GBM.
    Methods: Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot were analyzed. In vivo, NSG mice were intracranially implanted with PRMT5-intact and -depleted GBMNS, treated with trametinib by daily oral gavage, and observed for tumor progression and mice survival rate.
    Results: PRMT5 depletion enhanced trametinib-induced cytotoxicity in GBMNS. PRMT5 knockdown significantly decreased trametinib-induced AKT and ERBB3 escape pathways. However, ERBB3 inhibition alone failed to block trametinib-induced AKT activity suggesting that the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib-treated GBMNS resulted from AKT inhibition and not ERBB3 inhibition. In orthotopic murine xenograft models, PRMT5-depletion extended the survival of tumor-bearing mice, and combination with trametinib further increased survival.
    Conclusion: Combined PRMT5/MEK inhibition synergistically inhibited GBM in animal models and is a promising strategy for GBM therapy.
    Keywords:  AKT; ERBB3; PRMT5; glioblastoma; trametinib
    DOI:  https://doi.org/10.1093/noajnl/vdac095
  3. Brain. 2022 Jul 28. pii: awac222. [Epub ahead of print]
    Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity.
    Rita Perelroizen, Bar Philosof, Noga Budick-Harmelin, Tom Chernobylsky, Ariel Ron, Rotem Katzir, Dor Shimon, Adi Tessler, Orit Adir, Anat Gaoni-Yogev, Tom Meyer, Avivit Krivitsky, Nuphar Shidlovsky, Asaf Madi, Eytan Ruppin, Lior Mayo.
      Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumour-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumour-associated astrocyte translatome revealed astrocytes initiate transcriptional programmes that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumour-associated macrophages and promotes a pro-tumourigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumour progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumour microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. These findings suggest that targeting astrocyte immunometabolic signalling may be useful in treating this uniformly lethal brain tumour.
    Keywords:  astrocytes; cholesterol; glioma
    DOI:  https://doi.org/10.1093/brain/awac222
  4. Neuro Oncol. 2022 Jul 28. pii: noac186. [Epub ahead of print]
    Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion.
    Ann T Chen, Yang Xiao, Xiangjun Tang, Mehdi Baqri, Xingchun Gao, Melanie Reschke, Wendy C Sheu, Gretchen Long, Yu Zhou, Gang Deng, Shenqi Zhang, Yanxiang Deng, Zhiliang Bai, Dongjoo Kim, Anita Huttner, Russell Kunes, Murat Günel, Jennifer Moliterno, W Mark Saltzman, Rong Fan, Jiangbing Zhou.
       BACKGROUND: Improved treatment of glioblastoma (GBM) needs to address tumor invasion, a hallmark of the disease that remains poorly understood. In this study, we profiled GBM invasion through integrative analysis of histological and single-cell RNA sequencing (scRNA-seq) data from ten patients.
    METHODS: Human histology samples, patient-derived xenograft mouse histology samples, and scRNA-seq data were collected from ten GBM patients. Tumor invasion was characterized and quantified at the phenotypic level using H&E and Ki-67 histology stains. Crystallin alpha B (CRYAB) and CD44 were identified as regulators of tumor invasion from scRNA-seq transcriptomic data and validated in vitro, in vivo, and in a mouse GBM resection model.
    RESULTS: At the cellular level, we found that invasive GBM are less dense and proliferative than their non-invasive counterparts. At the molecular level, we identified unique transcriptomic features that significantly contribute to GBM invasion. Specifically, we found that CRYAB significantly contributes to post-operative recurrence and is highly co-expressed with CD44 in invasive GBM samples.
    CONCLUSIONS: Collectively, our analysis identifies differentially expressed features between invasive and nodular GBM, and describes a novel relationship between CRYAB and CD44 that contributes to tumor invasiveness, establishing a cellular and molecular landscape of GBM invasion.
    Keywords:  CRYAB; Glioblastoma; invasion; post-operative recurrence; single-cell RNA sequencing
    DOI:  https://doi.org/10.1093/neuonc/noac186
  5. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac102
    Butterfly glioblastoma: Clinical characteristics, treatment strategies and outcomes in a population-based cohort.
    Line Sagerup Bjorland, Kathinka Dæhli Kurz, Øystein Fluge, Bjørnar Gilje, Rupavathana Mahesparan, Hege Sætran, Anastasia Ushakova, Elisabeth Farbu.
       Background: Butterfly glioblastoma is a rare subgroup of glioblastoma with a bihemispheric tumor crossing the corpus callosum, and is associated with a dismal prognosis. Prognostic factors are previously sparsely described and optimal treatment remains uncertain. We aimed to analyze clinical characteristics, treatment strategies, and outcomes from butterfly glioblastoma in a real-world setting.
    Methods: This retrospective population-based cohort study included patients diagnosed with butterfly glioblastoma in Western Norway between 01/01/2007 and 31/12/2014. We enrolled patients with histologically confirmed glioblastoma and patients with a diagnosis based on a typical MRI pattern. Clinical data were extracted from electronic medical records. Molecular and MRI volumetric analyses were retrospectively performed. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards regression models.
    Results: Among 381 patients diagnosed with glioblastoma, 33 patients (8.7%) met the butterfly glioblastoma criteria. Median overall survival was 5.5 months (95% CI 3.1-7.9) and 3-year survival was 9.1%. Hypofractionated radiation therapy with or without temozolomide was the most frequently used treatment strategy, given to 16 of the 27 (59.3%) patients receiving radiation therapy. Best supportive care was associated with poorer survival compared with multimodal treatment [adjusted hazard ratio 5.11 (95% CI 1.09-23.89)].
    Conclusion: Outcome from butterfly glioblastoma was dismal, with a median overall survival of less than 6 months. However, long-term survival was comparable to that observed in non-butterfly glioblastoma, and multimodal treatment was associated with longer survival. This suggests that patients with butterfly glioblastoma may benefit from a more aggressive treatment approach despite the overall poor prognosis.
    Keywords:  3D volumetric; bihemispheric glioma; butterfly glioblastoma; clinical outcomes; survival
    DOI:  https://doi.org/10.1093/noajnl/vdac102
  6. Nat Commun. 2022 Jul 25. 13(1): 4268
    Integrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis.
    Eunnyung Bae, Ping Huang, Gaёlle Müller-Greven, Dolores Hambardzumyan, Andrew Edward Sloan, Amy S Nowacki, Nicholas Marko, Cathleen R Carlin, Candece L Gladson.
      Therapeutic targeting of angiogenesis in glioblastoma has yielded mixed outcomes. Investigation of tumor-associated angiogenesis has focused on the factors that stimulate the sprouting, migration, and hyperproliferation of the endothelial cells. However, little is known regarding the processes underlying the formation of the tumor-associated vessels. To address this issue, we investigated vessel formation in CD31+ cells isolated from human glioblastoma tumors. The results indicate that overexpression of integrin α3β1 plays a central role in the promotion of tube formation in the tumor-associated endothelial cells in glioblastoma. Blocking α3β1 function reduced sprout and tube formation in the tumor-associated endothelial cells and vessel density in organotypic cultures of glioblastoma. The data further suggest a mechanistic model in which integrin α3β1-promoted calcium influx stimulates macropinocytosis and directed maturation of the macropinosomes in a manner that promotes lysosomal exocytosis during nascent lumen formation. Altogether, our data indicate that integrin α3β1 may be a therapeutic target on the glioblastoma vasculature.
    DOI:  https://doi.org/10.1038/s41467-022-31981-2
  7. Science. 2022 Jul 29. 377(6605): 502-511
    Mechanism-based design of agents that selectively target drug-resistant glioma.
    Kingson Lin, Susan E Gueble, Ranjini K Sundaram, Eric D Huseman, Ranjit S Bindra, Seth B Herzon.
      Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O6-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.
    DOI:  https://doi.org/10.1126/science.abn7570
  8. Neuro Oncol. 2022 Jul 27. pii: noac183. [Epub ahead of print]
    The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models.
    Romain Sigaud, Lisa Rösch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Florian Selt, Sara Najafi, Simay Ayhan, Xenia F Gerloff, Nina Hofmann, Isabel Büdenbender, Lukas Schmitt, Kathrin I Foerster, Jürgen Burhenne, Walter E Haefeli, Andrey Korshunov, Felix Sahm, Cornelis M van Tilburg, David T W Jones, Stefan M Pfister, Deborah Knoerzer, Brent L Kreider, Max Sauter, Kristian W Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde.
       BACKGROUND: Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors.
    METHODS: We investigated the anti-tumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAF V600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing.
    RESULTS: Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of anti-proliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival.
    CONCLUSIONS: These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.
    Keywords:  BH3-mimetics; ERK inhibitor; MAPK inhibitor; pediatric low-grade glioma; synergism
    DOI:  https://doi.org/10.1093/neuonc/noac183
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