bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021–11–14
twenty-two papers selected by
Oltea Sampetrean, Keio University
  1. Novel Insights into the Role of the Mineralocorticoid Receptor in Human Glioblastoma.
  2. SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme.
  3. Isocitrate Dehydrogenase Wild-type Glial Tumors, Including Glioblastoma.
  4. Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts.
  5. Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells.
  6. Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR.
  7. Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma.
  8. Chronic pathophysiological changes in the normal brain parenchyma caused by radiotherapy accelerate glioma progression.
  9. New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma.
  10. Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment.
  11. Identification of five important genes to predict glioblastoma subtypes.
  12. Novel Ion Channel Targets and Drug Delivery Tools for Controlling Glioblastoma Cell Invasiveness.
  13. Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells.
  14. Proteomic Distributions in CD34+ Microvascular Niche Patterns of Glioblastoma.
  15. Long telomeres in need of a SNP: Germline contributions of telomere maintenance to glioma.
  16. An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma.
  17. In vitro evaluation of CAR-T cells in patient-derived glioblastoma models.
  18. The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
  19. Integration of Raman spectra with transcriptome data in glioblastoma multiforme defines tumour subtypes and predicts patient outcome.
  20. Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies.
  21. CAR T Cell Therapy's Potential for Pediatric Brain Tumors.
  22. T-Cell Immunotherapy for Pediatric High-Grade Gliomas: New Insights to Overcoming Therapeutic Challenges.
  1. Int J Mol Sci. 2021 Oct 28. pii: 11656. [Epub ahead of print]22(21):
    Novel Insights into the Role of the Mineralocorticoid Receptor in Human Glioblastoma.
    Paula Aldaz, Amaya Fernández-Celis, Natalia López-Andrés, Imanol Arozarena.
      The majority of glioblastoma (GBM) patients require the administration of dexamethasone (DEXA) to reduce brain inflammation. DEXA activates the glucocorticoid receptor (GR), which can consequently crosstalk with the mineralocorticoid receptor (MR). However, while GR signaling is well studied in GBM, little is known about the MR in brain tumors. We examined the implication of the MR in GBM considering its interplay with DEXA. Together with gene expression studies in patient cohorts, we used human GBM cell lines and patient-derived glioma stem cells (GSCs) to assess the impact of MR activation and inhibition on cell proliferation, response to radiotherapy, and self-renewal capacity. We show that in glioma patients, MR expression inversely correlates with tumor grade. Furthermore, low MR expression correlates with poorer survival in low grade glioma while in GBM the same applies to classical and mesenchymal subtypes, but not proneural tumors. MR activation by aldosterone suppresses the growth of some GBM cell lines and GSC self-renewal. In GBM cells, the MR antagonist spironolactone (SPI) can promote proliferation, radioprotection and cooperate with DEXA. In summary, we propose that MR signaling is anti-proliferative in GBM cells and blocks the self-renewal of GSCs. Contrary to previous evidence obtained in other cancer types, our results suggest that SPI has no compelling anti-neoplastic potential in GBM.
    Keywords:  dexamethasone; glioma; glucocorticoid receptor; mineralocorticoid receptor; spironolactone
    DOI:  https://doi.org/10.3390/ijms222111656
  2. Cancers (Basel). 2021 Oct 27. pii: 5393. [Epub ahead of print]13(21):
    SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme.
    Sophie Guelfi, Béatrice Orsetti, Virginie Deleuze, Valérie Rigau, Luc Bauchet, Hugues Duffau, Bernard Rothhut, Jean-Philippe Hugnot.
      Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.
    Keywords:  GBM microenvironment; GSC growth; SLUG (SNAI2); TAL1 (SCL); TGF-β signaling; endothelial cells; glioblastoma multiforme (GBM); glioblastoma stem cells (GSC); notch signaling; transcription factors
    DOI:  https://doi.org/10.3390/cancers13215393
  3. Hematol Oncol Clin North Am. 2021 Oct 29. pii: S0889-8588(21)00110-6. [Epub ahead of print]
    Isocitrate Dehydrogenase Wild-type Glial Tumors, Including Glioblastoma.
    Evanthia Galanis, Patrick Y Wen, John F de Groot, Michael Weller.
      Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial tumors include a wide spectrum of tumors with differences in prognosis and recommended therapeutic approaches. Tumors characterized as molecular glioblastoma in the World Health Organization 2021 classification should be treated according to the glioblastoma therapeutic principles and included in glioblastoma trials. Improving on existing treatments options including targeted and immunotherapy approaches is imperative for most patients with IDH wild-type glial tumors, and enrollment in clinical trials is encouraged.
    Keywords:  Glioblastoma; Glioma; H3K27M mutant glioma; IDH wild-type; Pilocytic astrocytoma; Pleomorphic xanthoastrocytoma
    DOI:  https://doi.org/10.1016/j.hoc.2021.08.007
  4. Int J Mol Sci. 2021 Oct 27. pii: 11633. [Epub ahead of print]22(21):
    Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts.
    Masashi Okada, Shuhei Suzuki, Keita Togashi, Asuka Sugai, Masahiro Yamamoto, Chifumi Kitanaka.
      Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.
    Keywords:  JNK; RFC-1; anti-folate; brain tumor initiating cells; glioma stem cell; serial transplantation assay
    DOI:  https://doi.org/10.3390/ijms222111633
  5. Cancers (Basel). 2021 Oct 21. pii: 5284. [Epub ahead of print]13(21):
    Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells.
    Sabbir Khan, Rajasekaran Mahalingam, Shayak Sen, Emmanuel Martinez-Ledesma, Arshad Khan, Kaitlin Gandy, Frederick F Lang, Erik P Sulman, Kristin D Alfaro-Munoz, Nazanin K Majd, Veerakumar Balasubramaniyan, John F de Groot.
      Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes. In addition, chronic inhibition of IFN/STAT1 signaling decreased cell proliferation and mesenchymal signatures in GSCs with intrinsically high IFN/STAT1 signaling. IFN-β exposure induced apoptosis in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by the pharmacological inhibitor ruxolitinib and STAT1 knockdown. We provide evidence for targeting IFN signaling in a specific sub-group of GBM patients. IFN-β may be a promising candidate for adjuvant GBM therapy.
    Keywords:  STAT1; apoptosis; cell proliferation; glioblastoma; glioma stem-like cell; interferon signaling
    DOI:  https://doi.org/10.3390/cancers13215284
  6. Cancers (Basel). 2021 Oct 24. pii: 5337. [Epub ahead of print]13(21):
    Lamellipodin-RICTOR Signaling Mediates Glioblastoma Cell Invasion and Radiosensitivity Downstream of EGFR.
    Stefanie Moritz, Matthias Krause, Jessica Schlatter, Nils Cordes, Anne Vehlow.
      Glioblastoma is a tumor type of unmet need despite the development of multimodal treatment strategies. The main factors contributing to the poor prognosis of glioblastoma patients are diverse genetic and epigenetic changes driving glioblastoma persistence and recurrence. Complemented are these factors by extracellular cues mediated through cell surface receptors, which further aid in fostering pro-invasion and pro-survival signaling contributing to glioblastoma therapy resistance. The underlying mechanisms conferring this therapy resistance are poorly understood. Here, we show that the cytoskeleton regulator Lamellipodin (Lpd) mediates invasiveness, proliferation and radiosensitivity of glioblastoma cells. Phosphoproteome analysis identified the epidermal growth factor receptor (EGFR) signaling axis commonly hyperactive in glioblastoma to depend on Lpd. Mechanistically, EGFR signaling together with an interaction between Lpd and the Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) jointly regulate glioblastoma radiosensitivity. Collectively, our findings demonstrate an essential function of Lpd in the radiation response and invasiveness of glioblastoma cells. Thus, we uncover a novel Lpd-driven resistance mechanism, which adds an additional critical facet to the complex glioblastoma resistance network.
    Keywords:  EGFR; Lamellipodin; RICTOR; glioblastoma; invasion; radiosensitivity
    DOI:  https://doi.org/10.3390/cancers13215337
  7. Oncogene. 2021 Nov 11.
    Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma.
    Gabriel Alzial, Ophelie Renoult, François Paris, Catherine Gratas, Anne Clavreul, Claire Pecqueur.
      Brain tumors actively reprogram their cellular metabolism to survive and proliferate, thus offering potential therapeutic opportunities. Over the past decade, extensive research has been done on mutant IDH enzymes as markers of good prognosis in glioblastoma, a highly aggressive brain tumor in adults with dismal prognosis. Yet, 95% of glioblastoma are IDH wild-type. Here, we review current knowledge about IDH wild-type enzymes and their putative role in mechanisms driving tumor progression. After a brief overview on tumor metabolic adaptation, we present the diverse metabolic function of IDH enzymes and their roles in glioblastoma initiation, progression and response to treatments. Finally, we will discuss wild-type IDH targeting in primary glioblastoma.
    DOI:  https://doi.org/10.1038/s41388-021-02056-1
  8. Sci Rep. 2021 Nov 11. 11(1): 22110
    Chronic pathophysiological changes in the normal brain parenchyma caused by radiotherapy accelerate glioma progression.
    Yuichiro Tsuji, Naosuke Nonoguchi, Daisuke Okuzaki, Yusuke Wada, Daisuke Motooka, Yuki Hirota, Taichiro Toho, Nobuhiko Yoshikawa, Motomasa Furuse, Shinji Kawabata, Shin-Ichi Miyatake, Hiroyuki Nakamura, Ryohei Yamamoto, Shota Nakamura, Toshihiko Kuroiwa, Masahiko Wanibuchi.
      Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-β1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.
    DOI:  https://doi.org/10.1038/s41598-021-01475-0
  9. Cancers (Basel). 2021 Oct 21. pii: 5280. [Epub ahead of print]13(21):
    New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma.
    Davis P Argersinger, Sarah R Rivas, Ashish H Shah, Sadhana Jackson, John D Heiss.
      H3K27M-mutant diffuse midline gliomas (DMGs) are rare childhood central nervous system tumors that carry a dismal prognosis. Thus, innovative treatment approaches are greatly needed to improve clinical outcomes for these patients. Here, we discuss current trends in research of H3K27M-mutant diffuse midline glioma. This review highlights new developments of molecular pathophysiology for these tumors, as they relate to epigenetics and therapeutic targeting. We focus our discussion on combinatorial therapies addressing the inherent complexity of treating H3K27M-mutant diffuse midline gliomas and incorporating recent advances in immunotherapy, molecular biology, genetics, radiation, and stereotaxic surgical diagnostics.
    Keywords:  H3K27M-mutant; biopsy; chemotherapy; diffuse intrinsic pontine glioma (DIPG); diffuse midline glioma; immunotherapy; radiotherapy
    DOI:  https://doi.org/10.3390/cancers13215280
  10. Cancers (Basel). 2021 Nov 04. pii: 5533. [Epub ahead of print]13(21):
    Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment.
    Samy Ajarrag, Yves St-Pierre.
      Traditional wisdom suggests that galectins play pivotal roles at different steps in cancer progression. Galectins are particularly well known for their ability to increase the invasiveness of cancer cells and their resistance to drug-induced cell death. They also contribute to the development of local and systemic immunosuppression, allowing cancer cells to escape the host's immunological defense. This is particularly true in glioma, the most common primary intracranial tumor. Abnormally high production of extracellular galectins in glioma contributes to the establishment of a strong immunosuppressive environment that favors immune escape and tumor progression. Considering the recent development and success of immunotherapy in halting cancer progression, it is logical to foresee that galectin-specific drugs may help to improve the success rate of immunotherapy for glioma. This provides a new perspective to target galectins, whose intracellular roles in cancer progression have already been investigated thoroughly. In this review, we discuss the mechanisms of action of galectins at different steps of glioma progression and the potential of galectin-specific drugs for the treatment of glioma.
    Keywords:  blood–brain barrier; brain tumors; galectin; glioblastoma; immunotherapy
    DOI:  https://doi.org/10.3390/cancers13215533
  11. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab144
    Identification of five important genes to predict glioblastoma subtypes.
    Yang Tang, Maleeha A Qazi, Kevin R Brown, Nicholas Mikolajewicz, Jason Moffat, Sheila K Singh, Paul D McNicholas.
       Background: Glioblastoma (GBM), the most common and aggressive primary brain tumour in adults, has been classified into three subtypes: classical, mesenchymal, and proneural. While the original classification relied on an 840 gene-set, further clarification on true GBM subtypes uses a 150-gene signature to accurately classify GBM into the three subtypes. We hypothesized whether a machine learning approach could be used to identify a smaller gene-set to accurately predict GBM subtype.
    Methods: Using a supervised machine learning approach, extreme gradient boosting (XGBoost), we developed a classifier to predict the three subtypes of glioblastoma (GBM): classical, mesenchymal, and proneural. We tested the classifier on in-house GBM tissue, cell lines, and xenograft samples to predict their subtype.
    Results: We identified the five most important genes for characterizing the three subtypes based on genes that often exhibited high Importance Scores in our XGBoost analyses. On average, this approach achieved 80.12% accuracy in predicting these three subtypes of GBM. Furthermore, we applied our five-gene classifier to successfully predict the subtype of GBM samples at our centre.
    Conclusion: Our 5-gene set classifier is the smallest classifier to date that can predict GBM subtypes with high accuracy, which could facilitate the future development of a five-gene subtype diagnostic biomarker for routine assays in GBM samples.
    Keywords:  XGBoost; classification; gene signature; glioblastoma subtypes; statistical learning
    DOI:  https://doi.org/10.1093/noajnl/vdab144
  12. Int J Mol Sci. 2021 Nov 02. pii: 11909. [Epub ahead of print]22(21):
    Novel Ion Channel Targets and Drug Delivery Tools for Controlling Glioblastoma Cell Invasiveness.
    Alanah Varricchio, Sunita A Ramesh, Andrea J Yool.
      Comprising more than half of all brain tumors, glioblastoma multiforme (GBM) is a leading cause of brain cancer-related deaths worldwide. A major clinical challenge is presented by the capacity of glioma cells to rapidly infiltrate healthy brain parenchyma, allowing the cancer to escape control by localized surgical resections and radiotherapies, and promoting recurrence in other brain regions. We propose that therapies which target cellular motility pathways could be used to slow tumor dispersal, providing a longer time window for administration of frontline treatments needed to directly eradicate the primary tumors. An array of signal transduction pathways are known to be involved in controlling cellular motility. Aquaporins (AQPs) and voltage-gated ion channels are prime candidates as pharmacological targets to restrain cell migration in glioblastoma. Published work has demonstrated AQPs 1, 4 and 9, as well as voltage-gated potassium, sodium and calcium channels, chloride channels, and acid-sensing ion channels are expressed in GBM and can influence processes of cell volume change, extracellular matrix degradation, cytoskeletal reorganization, lamellipodial and filopodial extension, and turnover of cell-cell adhesions and focal assembly sites. The current gap in knowledge is the identification of optimal combinations of targets, inhibitory agents, and drug delivery systems that will allow effective intervention with minimal side effects in the complex environment of the brain, without disrupting finely tuned activities of neuro-glial networks. Based on published literature, we propose that co-treatments using AQP inhibitors in addition to other therapies could increase effectiveness, overcoming some limitations inherent in current strategies that are focused on single mechanisms. An emerging interest in nanobodies as drug delivery systems could be instrumental for achieving the selective delivery of combinations of agents aimed at multiple key targets, which could enhance success in vivo.
    Keywords:  CaV channel; KV channel; NaV channel; aquaporin; brain cancer; glioblastoma; glioma; membrane intrinsic protein; migration; motility
    DOI:  https://doi.org/10.3390/ijms222111909
  13. Int J Mol Sci. 2021 Nov 03. pii: 11938. [Epub ahead of print]22(21):
    Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells.
    Luca X Zampieri, Martina Sboarina, Andrea Cacace, Debora Grasso, Léopold Thabault, Loïc Hamelin, Thibaut Vazeille, Elodie Dumon, Rodrigue Rossignol, Raphaël Frédérick, Etienne Sonveaux, Florence Lefranc, Pierre Sonveaux.
      Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.
    Keywords:  PARP inhibitors; cancer metabolism; chemoresistance; glioblastoma; metformin; mitochondria; temozolomide (TMZ)
    DOI:  https://doi.org/10.3390/ijms222111938
  14. J Histochem Cytochem. 2021 Nov 09. 221554211058098
    Proteomic Distributions in CD34+ Microvascular Niche Patterns of Glioblastoma.
    Jintao Chen, Sifeng Mao, Ziyi He, Lijuan Yang, Jinfeng Zhang, Jin-Ming Lin, Zhi-Xiong Lin.
      The poor clinical prognosis and microvascular patterns of glioblastoma (GBM) are of serious concern to many clinicians and researchers. However, very few studies have examined the correlation between microvascular niche patterns (MVNPs) and proteomic distribution. In this study, CD34 immunofluorescence staining and matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-IMS) technology were used to investigate the protein distributions in MVNPs. CD34+ microvascular phenotype could be divided into four types: microvascular sprouting (MS), vascular cluster (VC), vascular garland (VG), and glomeruloid vascular proliferation (GVP). Based on such characteristics, MVNPs were divided into two types by cluster analysis, namely, type I, comprising primarily MS and VC, and type II, comprising many VGs and GVPs. Survival analysis indicated the type of MVNPs to be an independent prognostic factor for progression-free and overall survival in GBM. MALDI-IMS results showed the peaks at m/z 1037 and 8960 to exhibit stronger ion signals in type II, while those at m/z 3240 and 3265 exhibited stronger ion signals in type I. The findings may assist future research on therapy and help predict prognosis in GBM. However, due to the limited number of studies, more well-designed studies are warranted to further verify our results.
    Keywords:  MALDI-imaging MS; angiogenesis; glioblastoma; microvascular; prognosis; stem cell; stemness; tumor heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.1369/00221554211058098
  15. Neuro Oncol. 2021 Nov 10. pii: noab260. [Epub ahead of print]
    Long telomeres in need of a SNP: Germline contributions of telomere maintenance to glioma.
    Linda Kachuri, Kyle M Walsh.
      
    DOI:  https://doi.org/10.1093/neuonc/noab260
  16. Cancers (Basel). 2021 Oct 22. pii: 5314. [Epub ahead of print]13(21):
    An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma.
    Kathleen M Storey, Trachette L Jackson.
      Oncolytic viral therapies and immunotherapies are of growing clinical interest due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. These treatment modalities provide promising alternatives to the standard of care, particularly for cancers with poor prognoses, such as the lethal brain tumor glioblastoma (GBM). However, uncertainty remains regarding optimal dosing strategies, including how the spatial location of viral doses impacts therapeutic efficacy and tumor landscape characteristics that are most conducive to producing an effective immune response. We develop a three-dimensional agent-based model (ABM) of GBM undergoing treatment with a combination of an oncolytic Herpes Simplex Virus and an anti-PD-1 immunotherapy. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We utilize the spatially explicit nature of the ABM to determine optimal viral dosing in both the temporal and spatial contexts. After proposing an adaptive viral dosing strategy that chooses to dose sites at the location of highest tumor cell density, we find that, in most cases, this adaptive strategy produces a more effective treatment outcome than repeatedly dosing in the center of the tumor.
    Keywords:  agent-based modeling; combination therapy; glioblastoma; immune checkpoint inhibitor; mathematical modeling; oncolytic viral therapy
    DOI:  https://doi.org/10.3390/cancers13215314
  17. STAR Protoc. 2021 Dec 17. 2(4): 100920
    In vitro evaluation of CAR-T cells in patient-derived glioblastoma models.
    Benjamin A Brakel, Chirayu R Chokshi, Sabra K Salim, Chitra Venugopal, Sheila Singh.
      Advances in chimeric antigen receptor (CAR) T cell therapies have led to the modality dominating translational cancer research; however, a standardized protocol for evaluating such therapies in vitro is needed. This protocol details the in vitro preclinical evaluation of CAR-T cell therapies for glioblastoma (GBM), including target cell cytotoxicity and T cell proliferation, activation, and cytokine release assays. For complete details on the use and execution of this protocol, please refer to Vora et al. (2020).
    Keywords:  Cancer; Cell culture; Cell separation/fractionation; Cell-based Assays; Flow Cytometry/Mass Cytometry; Health Sciences; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2021.100920
  18. PLoS Genet. 2021 Nov 09. 17(11): e1009868
    The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma.
    Irena Bočkaj, Tosca E I Martini, Eduardo S de Camargo Magalhães, Petra L Bakker, Tiny G J Meeuwsen-de Boer, Inna Armandari, Saskia L Meuleman, Marin T Mondria, Colin Stok, Yannick P Kok, Bjorn Bakker, René Wardenaar, Jonas Seiler, Mathilde J C Broekhuis, Hilda van den Bos, Diana C J Spierings, Femke C A Ringnalda, Hans Clevers, Ulrich Schüller, Marcel A T M van Vugt, Floris Foijer, Sophia W M Bruggeman.
      While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development.
    DOI:  https://doi.org/10.1371/journal.pgen.1009868
  19. J Cell Mol Med. 2021 Nov 12.
    Integration of Raman spectra with transcriptome data in glioblastoma multiforme defines tumour subtypes and predicts patient outcome.
    Pierre-Jean Le Reste, Eleftherios Pilalis, Marc Aubry, Mari McMahon, Luis Cano, Amandine Etcheverry, Aristotelis Chatziioannou, Eric Chevet, Alain Fautrel.
      Raman spectroscopy is an imaging technique that has been applied to assess molecular compositions of living cells to characterize cell types and states. However, owing to the diverse molecular species in cells and challenges of assigning peaks to specific molecules, it has not been clear how to interpret cellular Raman spectra. Here, we provide firm evidence that cellular Raman spectra (RS) and transcriptomic profiles of glioblastoma can be computationally connected and thus interpreted. We find that the dimensions of high-dimensional RS and transcriptomes can be reduced and connected linearly through a shared low-dimensional subspace. Accordingly, we were able to predict global gene expression profiles by applying the calculated transformation matrix to Raman spectra and vice versa. From these analyses, we extract a minimal gene expression signature associated with specific RS profiles and predictive of disease outcome.
    Keywords:  Raman spectroscopy; data integration; glioblastoma
    DOI:  https://doi.org/10.1111/jcmm.16902
  20. Oncogene. 2021 Nov 10.
    Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies.
    Izac J Findlay, Geoffry N De Iuliis, Ryan J Duchatel, Evangeline R Jackson, Nicholas A Vitanza, Jason E Cain, Sebastian M Waszak, Matthew D Dun.
      Diffuse midline glioma (DMG) is a deadly pediatric and adolescent central nervous system (CNS) tumor localized along the midline structures of the brain atop the spinal cord. With a median overall survival (OS) of just 9-11-months, DMG is characterized by global hypomethylation of histone H3 at lysine 27 (H3K27me3), driven by recurring somatic mutations in H3 genes including, HIST1H3B/C (H3.1K27M) or H3F3A (H3.3K27M), or through overexpression of EZHIP in patients harboring wildtype H3. The recent World Health Organization's 5th Classification of CNS Tumors now designates DMG as, 'H3 K27-altered', suggesting that global H3K27me3 hypomethylation is a ubiquitous feature of DMG and drives devastating transcriptional programs for which there are no treatments. H3-alterations co-segregate with various other somatic driver mutations, highlighting the high-level of intertumoral heterogeneity of DMG. Furthermore, DMG is also characterized by very high-level intratumoral diversity with tumors harboring multiple subclones within each primary tumor. Each subclone contains their own combinations of driver and passenger lesions that continually evolve, making precision-based medicine challenging to successful execute. Whilst the intertumoral heterogeneity of DMG has been extensively investigated, this is yet to translate to an increase in patient survival. Conversely, our understanding of the non-genomic factors that drive the rapid growth and fatal nature of DMG, including endogenous and exogenous microenvironmental influences, neurological cues, and the posttranscriptional and posttranslational architecture of DMG remains enigmatic or at best, immature. However, these factors are likely to play a significant role in the complex biological sequelae that drives the disease. Here we summarize the heterogeneity of DMG and emphasize how analysis of the posttranslational architecture may improve treatment paradigms. We describe factors that contribute to treatment response and disease progression, as well as highlight the potential for pharmaco-proteogenomics (i.e., the integration of genomics, proteomics and pharmacology) in the management of this uniformly fatal cancer.
    DOI:  https://doi.org/10.1038/s41388-021-02102-y
  21. Cancers (Basel). 2021 Oct 29. pii: 5445. [Epub ahead of print]13(21):
    CAR T Cell Therapy's Potential for Pediatric Brain Tumors.
    Pauline Thomas, Natacha Galopin, Emma Bonérandi, Béatrice Clémenceau, Sophie Fougeray, Stéphane Birklé.
      Malignant central nervous system tumors are the leading cause of cancer death in children. Progress in high-throughput molecular techniques has increased the molecular understanding of these tumors, but the outcomes are still poor. Even when efficacious, surgery, radiation, and chemotherapy cause neurologic and neurocognitive morbidity. Adoptive cell therapy with autologous CD19 chimeric antigen receptor T cells (CAR T) has demonstrated remarkable remission rates in patients with relapsed refractory B cell malignancies. Unfortunately, tumor heterogeneity, the identification of appropriate target antigens, and location in a growing brain behind the blood-brain barrier within a specific suppressive immune microenvironment restrict the efficacy of this strategy in pediatric neuro-oncology. In addition, the vulnerability of the brain to unrepairable tissue damage raises important safety concerns. Recent preclinical findings, however, have provided a strong rationale for clinical trials of this approach in patients. Here, we examine the most important challenges associated with the development of CAR T cell immunotherapy and further present the latest preclinical strategies intending to optimize genetically engineered T cells' efficiency and safety in the field of pediatric neuro-oncology.
    Keywords:  T cell; atypical teratoid rhabdoid tumors; chimeric antigen receptor; ependymoma; high-grade glioma; medulloblastoma; pediatric brain tumor; radiotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13215445
  22. Front Oncol. 2021 ;11 718030
    T-Cell Immunotherapy for Pediatric High-Grade Gliomas: New Insights to Overcoming Therapeutic Challenges.
    Dalia Haydar, Jorge Ibañez-Vega, Giedre Krenciute.
      Despite decades of research, pediatric central nervous system (CNS) tumors remain the most debilitating, difficult to treat, and deadliest cancers. Current therapies, including radiation, chemotherapy, and/or surgery, are unable to cure these diseases and are associated with serious adverse effects and long-term impairments. Immunotherapy using chimeric antigen receptor (CAR) T cells has the potential to elucidate therapeutic antitumor immune responses that improve survival without the devastating adverse effects associated with other therapies. Yet, despite the outstanding performance of CAR T cells against hematologic malignancies, they have shown little success targeting brain tumors. This lack of efficacy is due to a scarcity of targetable antigens, interactions with the immune microenvironment, and physical and biological barriers limiting the homing and trafficking of CAR T cells to brain tumors. In this review, we summarize experiences with CAR T-cell therapy for pediatric CNS tumors in preclinical and clinical settings and focus on the current roadblocks and novel strategies to potentially overcome those therapeutic challenges.
    Keywords:  CAR T cells therapy; childhood CNS tumors; immune tumor microenvironment; immunotherapy; pediatric-type diffuse high-grade glioma; tumor antigen
    DOI:  https://doi.org/10.3389/fonc.2021.718030
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