bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–09–04
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Glioblastoma CD105+ cells define a SOX2- cancer stem cell-like subpopulation in the pre-invasive niche.
  2. Targeting drug-resistant glioblastoma.
  3. Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE.
  4. Curcumin-based-fluorescent probes targeting ALDH1A3 as a promising tool for glioblastoma precision surgery and early diagnosis.
  5. Multifunctional mRNA-based CAR T cells display promising anti-tumor activity against glioblastoma.
  6. Molecular Crosstalk between T Cells and Tumor Uncovers GBM-Specific T Cell Signatures in Blood: Noninvasive GBM Diagnosis Using Immunosensors.
  7. In Vivo Functional Characterization of EGFR Variants Identifies Novel Drivers of Glioblastoma.
  8. Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy.
  9. Mechanosensitive expression of the mesenchymal subtype marker connective tissue growth factor in glioblastoma.
  10. Tumor spheroids accelerate persistently invading cancer cells.
  11. Dual role of pseudogene TMEM198B in promoting lipid metabolism and immune escape of glioma cells.
  12. Ascorbate content of clinical glioma tissues is related to tumour grade and to global levels of 5-hydroxymethyl cytosine.
  13. Quantification of spatial subclonal interactions enhancing the invasive phenotype of pediatric glioma.
  1. Acta Neuropathol Commun. 2022 Aug 29. 10(1): 126
    Glioblastoma CD105+ cells define a SOX2- cancer stem cell-like subpopulation in the pre-invasive niche.
    Jiaxin Li, Fredrik Ek, Roger Olsson, Mattias Belting, Johan Bengzon.
      Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105+) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105+ cells were isolated and assessed for stem-like characteristics. In vitro, CD105+ cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105+ cells were characterized by Nestin+, Vimentin+ and SOX2-, clearly distinguishing them from SOX2+ GCS. GBM CD105+ cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105+ cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105+ cells. Finally, screening for 88 clinical drugs revealed that GBM CD105+ cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105+ cells in order to reshape the tumor microenvironment and block GBM progression.
    Keywords:  CD105; Drug screening; Exome sequencing; Glioma stem-like cell; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40478-022-01422-8
  2. Nat Rev Drug Discov. 2022 Aug 31.
    Targeting drug-resistant glioblastoma.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-022-00146-7
  3. iScience. 2022 Sep 16. 25(9): 104872
    Hypoxia-induced HMGB1 promotes glioma stem cells self-renewal and tumorigenicity via RAGE.
    Cuifang Ye, Huan Li, Yachao Li, Yang Zhang, Guohao Liu, Hailong Mi, Honglian Li, Qungen Xiao, Li Niu, Xingjiang Yu.
      Glioma stem cells (GSCs) in the hypoxic niches contribute to tumor initiation, progression, and recurrence in glioblastoma (GBM). Hypoxia induces release of high-mobility group box 1 (HMGB1) from tumor cells, promoting the development of tumor. Here, we report that HMGB1 is overexpressed in human GBM specimens. Hypoxia promotes the expression and secretion of HMGB1 in GSCs. Furthermore, silencing HMGB1 results in the loss of stem cell markers and a reduction in self-renewal ability of GSCs. Additionally, HMGB1 knockdown inhibits the activation of RAGE-dependent ERK1/2 signaling pathway and arrests the cell cycle in GSCs. Consistently, FPS-ZM1, an inhibitor of RAGE, downregulates HMGB1 expression and the phosphorylation of ERK1/2, leading to a reduction in the proliferation of GSCs. In xenograft mice of GBM, HMGB1 knockdown inhibits tumor growth and promotes mouse survival. Collectively, these findings uncover a vital function for HMGB1 in regulating GSC self-renewal potential and tumorigenicity.
    Keywords:  Biological sciences; Cancer; Cell biology; Microenvironment; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104872
  4. Commun Biol. 2022 Sep 01. 5(1): 895
    Curcumin-based-fluorescent probes targeting ALDH1A3 as a promising tool for glioblastoma precision surgery and early diagnosis.
    Edoardo L M Gelardi, Diego Caprioglio, Giorgia Colombo, Erika Del Grosso, Daniele Mazzoletti, Daiana Mattoteia, Stefano Salamone, Davide M Ferraris, Eleonora Aronica, Giulia Nato, Annalisa Buffo, Menico Rizzi, Lorenzo Magrassi, Alberto Minassi, Silvia Garavaglia.
      Glioblastoma (GBM) is the most aggressive primary brain tumour for which both effective treatments and efficient tools for an early-stage diagnosis are lacking. Herein, we present curcumin-based fluorescent probes that are able to bind to aldehyde dehydrogenase 1A3 (ALDH1A3), an enzyme overexpressed in glioma stem cells (GSCs) and associated with stemness and invasiveness of GBM. Two compounds are selective versus ALDH1A3, without showing any appreciable interaction with other ALDH1A isoenzymes. Indeed, their fluorescent signal is detectable only in our positive controls in vitro and absent in cells that lack ALDH1A3. Remarkably, in vivo, our Probe selectively accumulate in glioblastoma cells, allowing the identification of the growing tumour mass. The significant specificity of our compounds is the necessary premise for their further development into glioblastoma cells detecting probes to be possibly used during neurosurgical operations.
    DOI:  https://doi.org/10.1038/s42003-022-03834-7
  5. Clin Cancer Res. 2022 Aug 29. pii: CCR-21-4384. [Epub ahead of print]
    Multifunctional mRNA-based CAR T cells display promising anti-tumor activity against glioblastoma.
    Hanna Meister, Thomas Look, Patrick Roth, Steve Pascolo, Ugur Sahin, Sohyon Lee, Benjamin D Hale, Berend Snijder, Luca Regli, Vidhya Ravi, Dieter Henrik Heiland, Charles L Sentman, Michael Weller, Tobias Weiss.
       PURPOSE: Most chimeric antigen receptor (CAR)-T cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes and the risk for uncontrollable off-tumor toxicities. mRNA-based T cell modifications are an emerging safe, rapid and cost-effective alternative to overcome these challenges, but are underexplored against glioblastoma.
    EXPERIMENTAL DESIGN: We generated mouse and human mRNA-based multifunctional T cells co-expressing a multitargeting CAR based on the NKG2D receptor and the pro-inflammatory cytokines IL12 and IFNa2 and assessed their anti-glioma activity in vitro and in vivo.
    RESULTS: Compared to T cells that either expressed the CAR or cytokines alone, multifunctional CAR T cells demonstrated increased anti-glioma activity in vitro and in vivo in three orthotopic immunocompetent mouse glioma models without signs of toxicity. Mechanistically, the co-expression of IL12 and IFNa2 in addition to the CAR promoted a pro-inflammatory tumor microenvironment and reduced T cell exhaustion as demonstrated by ex vivo immune phenotyping, cytokine profiling and RNA sequencing. The translational potential was demonstrated by image-based single-cell analyses of mRNA-modified T cells in patient glioblastoma samples with a complex cellular microenvironment. This revealed strong anti-glioma activity of human mRNA-based multifunctional NKG2D CAR T cells co-expressing IL12 and IFNa2 whereas T cells that expressed either the CAR or cytokines alone did not demonstrate comparable anti-glioma activity.
    CONCLUSION: These data provide a robust rationale for future clinical studies with mRNA-based multifunctional CAR T cells to treat malignant brain tumors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-4384
  6. ACS Nano. 2022 Aug 30.
    Molecular Crosstalk between T Cells and Tumor Uncovers GBM-Specific T Cell Signatures in Blood: Noninvasive GBM Diagnosis Using Immunosensors.
    Ashok Kumar Dhinakaran, Priya Dharmalingam, Swarna Ganesh, Krishnan Venkatakrishnan, Sunit Das, Bo Tan.
      Glioblastoma (GBM) is the most common and aggressive stage IV brain cancer with a poor prognosis and survival rate. The blood-brain barrier (BBB) in GBM prevents the entry and exit of biomarkers, limiting its treatment options. Hence, GBM diagnosis is pivotal for timely clinical management. Currently, there exists no clinically validated biomarker for GBM diagnosis. T cells exhibit the potential to escape a leaky BBB in GBM patients. These T cells infiltrating the GBM interact with the heterogeneous population of tumor cells, display a symbiotic interaction resulting in intertwined molecular crosstalk, and display a GBM-associated signature while entering the peripheral circulation. Therefore, we hypothesize that studying these distinct molecular changes is critical to enable T cells to be a diagnostic marker for accurate detection of GBM from patient blood. We demonstrated this by utilizing the phenotypic and immunological landscape changes in T cells associated with glioblastoma tumors. GBM exhibits a high level of heterogeneity with diverse subtypes of cells within the tumor, enabling immune infiltration and different degrees of interactions with the tumor. To accurately detect these subtle molecular differences in T cells, we designed an immunosensor with a high detection sensitivity and repeatability. Hence in this study, we investigated the characteristic behavior of T cells to establish two preclinically validated biomarkers: GBM-associated T cells (GBMAT) and GBM stem cell-associated T cells (GSCAT). A comprehensive investigation was conducted by mimicking the tumor microenvironment in vitro by coculturing T cells with cancer cells and cancer stem cells to study the distinct variation in GBMAT and GSCAT. Preclinical investigation of T cells from GBM patient blood shows similar characteristics to our established biomarkers (GBMAT, GSCAT). Further evaluating the relative attributes of T cells in patient blood and tissue biopsy confirms the infiltrating ability of T cells across the BBB. A pilot validation using a SERS-based machine learning algorithm was accomplished by training the model with GBMAT and GSCAT as diagnostic markers. Using GBMAT as a biomarker, we achieved a sensitivity and specificity of 93.3% and 97.4%, respectively, whereas applying GSCAT yielded a sensitivity and specificity of 100% and 98.7%, respectively. We also validated this diagnostic methodology by using conventional biological assays to study the change in expression levels of T cell surface markers (CD4 and CD8) and cytokine levels in T cells (IL6, IL10, TNFα, INFγ) from GBM patients. This study introduces T cells as GBM-specific immune biomarkers to diagnose GBM using patient liquid biopsy. This preclinical validation study presents a better translatability into clinical reality that will enable rapid and noninvasive glioblastoma detection from patient blood.
    Keywords:  SERS; T cell; glioblastoma; glioblastoma stem cells; sensors
    DOI:  https://doi.org/10.1021/acsnano.2c04160
  7. Neuro Oncol. 2022 Aug 31. pii: noac215. [Epub ahead of print]
    In Vivo Functional Characterization of EGFR Variants Identifies Novel Drivers of Glioblastoma.
    Kwanha Yu, Kathleen Kong, Brittney Lozzi, Estefania Luna-Figueroa, Alexis Cervantes, Rachel Curry, Carrie A Mohila, Ganesh Rao, Ali Jalali, Gordon B Mills, Kenneth L Scott, Benjamin Deneen.
       BACKGROUND: Glioblastoma is the most common and aggressive primary brain tumor. Large scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering "driver" and "passenger" events amongst the vast volume of information.
    METHODS: We utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased lipidomics screen.
    RESULTS: Our screen identified A289I as the most potent EGFR variant, which has previously not been characterized. One of the mechanisms through with A289I promotes gliomagenesis is to alter cellular triacylglycerides through MTTP. Knockout of Mttp in mouse gliomas, reduces gliomagenesis in multiple models.
    CONCLUSION: EGFR variants that differ by a single amino acid residue differentially promote gliomagenesis. Among the identified mechanism that drive glioma growth include lipid metabolism through MTTP. Understanding triacylglyceride accumulation may present a prospective therapeutic pathway for this deadly disease.
    Keywords:  EGFR variants; Glioblastoma; lipid metabolism; mouse models
    DOI:  https://doi.org/10.1093/neuonc/noac215
  8. Nat Commun. 2022 Sep 01. 13(1): 5127
    Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy.
    Rong Sun, Mingzhu Liu, Jianping Lu, Binbin Chu, Yunmin Yang, Bin Song, Houyu Wang, Yao He.
      Bacteria can bypass the blood-brain barrier (BBB), suggesting the possibility of employment of bacteria for combating central nervous system diseases. Herein, we develop a bacteria-based drug delivery system for glioblastoma (GBM) photothermal immunotherapy. The system, which we name as 'Trojan bacteria', consists of bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected bacteria bypass the BBB, targeting and penetrating GBM tissues. Upon 808 nm-laser irradiation, the photothermal effects produced by ICG allow the destruction of bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual bacteria are effectively eliminated from the body, supporting the potential therapeutic use of this system.
    DOI:  https://doi.org/10.1038/s41467-022-32837-5
  9. Sci Rep. 2022 Sep 02. 12(1): 14982
    Mechanosensitive expression of the mesenchymal subtype marker connective tissue growth factor in glioblastoma.
    Thomas James Grundy, Louise Orcheston-Findlay, Eshana de Silva, Thuvarahan Jegathees, Victoria Prior, Farhana Amy Sarker, Geraldine Margaret O'Neill.
      Mechanical forces created by the extracellular environment regulate biochemical signals that modulate the inter-related cellular phenotypes of morphology, proliferation, and migration. A stiff microenvironment induces glioblastoma (GBM) cells to develop prominent actin stress fibres, take on a spread morphology and adopt trapezoid shapes, when cultured in 2D, which are phenotypes characteristic of a mesenchymal cell program. The mesenchymal subtype is the most aggressive among the molecular GBM subtypes. Recurrent GBM have been reported to transition to mesenchymal. We therefore sought to test the hypothesis that stiffer microenvironments-such as those found in different brain anatomical structures and induced following treatment-contribute to the expression of markers characterising the mesenchymal subtype. We cultured primary patient-derived cell lines that reflect the three common GBM subtypes (mesenchymal, proneural and classical) on polyacrylamide (PA) hydrogels with controlled stiffnesses spanning the healthy and pathological tissue range. We then assessed the canonical mesenchymal markers Connective Tissue Growth Factor (CTGF) and yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) expression, via immunofluorescence. Replating techniques and drug-mediated manipulation of the actin cytoskeleton were utilised to ascertain the response of the cells to differing mechanical environments. We demonstrate that CTGF is induced rapidly following adhesion to a rigid substrate and is independent of actin filament formation. Collectively, our data suggest that microenvironmental rigidity can stimulate expression of mesenchymal-associated molecules in GBM.
    DOI:  https://doi.org/10.1038/s41598-022-19175-8
  10. Sci Rep. 2022 Aug 29. 12(1): 14713
    Tumor spheroids accelerate persistently invading cancer cells.
    Melanie Audoin, Maria Tangen Søgaard, Liselotte Jauffred.
      Glioblastoma brain tumors form in the brain's white matter and remain one of the most lethal cancers despite intensive therapy and surgery. The complex morphology of these tumors includes infiltrative growth and gain of cell motility. Therefore, various brain-mimetic model systems have been developed to investigate invasion dynamics. Despite this, exactly how gradients of cell density, chemical signals and metabolites influence individual cells' migratory behavior remains elusive. Here we show that the gradient field induced by the spheroid-accelerates cells' invasion of the extracellular matrix. We show that cells are pushed away from the spheroid along a radial gradient, as predicted by a biased persistent random walk. Thus, our results grasp in a simple model the complex behavior of metastasizing cells. We anticipate that this well-defined and quantitative assay could be instrumental in the development of new anti-cancer strategies.
    DOI:  https://doi.org/10.1038/s41598-022-18950-x
  11. Oncogene. 2022 Aug 29.
    Dual role of pseudogene TMEM198B in promoting lipid metabolism and immune escape of glioma cells.
    Ying Zhan, Wei Qiao, Bolong Yi, Xinyu Yang, Miaomiao Li, Lu Sun, Lian Ji, Peng Su, Xin Wang, Furong Zhang, Rui Zhang, Mingjun Gao, Wujun Zhao, Yichen Song.
      Dysregulation of pseudogenes, enhancement of fatty acid synthesis and formation of immunosuppressive microenvironment are important factors that promote the malignant progression of glioma. It is of great significance to search for the molecular mechanism of interaction between the three and then perform targeted interference for improving the treatment of glioma. In this study, we found that pseudogene transmembrane protein 198B (TMEM198B) was highly expressed in glioma tissues and cell lines, and it could promote malignant progression of glioma by regulating lipid metabolism reprogramming and remodeling immune microenvironment. Applying the experimental methods of gene interference, lipidomics and immunology, we further confirmed that TMEM198B promoted PLAG1 like zinc finger 2 (PLAGL2) expression by mediating tri-methylation of histone H3 on lysine 4 (H3K4me3) of PLAGL2 through binding to SET domain containing 1B (SETD1B). Increased PLAGL2 could transcriptional activate ATP citrate lyase (ACLY) and ELOVL fatty acid elongase 6 (ELOVL6) expression, and then influenced the biological behaviors of glioma cells via enhancing the de novo lipogenesis and fatty acid acyl chain elongation. At the same time, TMEM198B promoted macrophages lipid accumulation and intensification of fatty acid oxidation (FAO) through glioma-derived exosomes (GDEs), further induced macrophages to M2 polarization, which subsequently facilitated immune escape of glioma cells. In conclusion, our present study clarifies that the TMEM198B/PLAGL2/ACLY/ELOVL6 pathway conducts crucial regulatory effects on the malignant progression of glioma, which provides novel targets and new ideas for molecular targeted therapy and immunotherapy of glioma.
    DOI:  https://doi.org/10.1038/s41388-022-02445-0
  12. Sci Rep. 2022 Sep 01. 12(1): 14845
    Ascorbate content of clinical glioma tissues is related to tumour grade and to global levels of 5-hydroxymethyl cytosine.
    Rebekah L I Crake, Eleanor R Burgess, George A R Wiggins, Nicholas J Magon, Andrew B Das, Margreet C M Vissers, Helen R Morrin, Janice A Royds, Tania L Slatter, Bridget A Robinson, Elisabeth Phillips, Gabi U Dachs.
      Gliomas are incurable brain cancers with poor prognosis, with epigenetic dysregulation being a distinctive feature. 5-hydroxymethylcytosine (5-hmC), an intermediate generated in the demethylation of 5-methylcytosine, is present at reduced levels in glioma tissue compared with normal brain, and that higher levels of 5-hmC are associated with improved patient survival. DNA demethylation is enzymatically driven by the ten-eleven translocation (TET) dioxygenases that require ascorbate as an essential cofactor. There is limited data on ascorbate in gliomas and the relationship between ascorbate and 5-hmC in gliomas has never been reported. Clinical glioma samples (11 low-grade, 26 high-grade) were analysed for ascorbate, global DNA methylation and hydroxymethylation, and methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Low-grade gliomas contained significantly higher levels of ascorbate than high-grade gliomas (p = 0.026). Levels of 5-hmC were significantly higher in low-grade than high-grade glioma (p = 0.0013). There was a strong association between higher ascorbate and higher 5-hmC (p = 0.004). Gliomas with unmethylated and methylated MGMT promoters had similar ascorbate levels (p = 0.96). One mechanism by which epigenetic modifications could occur is through ascorbate-mediated optimisation of TET activity in gliomas. These findings open the door to clinical intervention trials in patients with glioma to provide both mechanistic information and potential avenues for adjuvant ascorbate therapy.
    DOI:  https://doi.org/10.1038/s41598-022-19032-8
  13. Cell Rep. 2022 Aug 30. pii: S2211-1247(22)01103-2. [Epub ahead of print]40(9): 111283
    Quantification of spatial subclonal interactions enhancing the invasive phenotype of pediatric glioma.
    Haider Tari, Ketty Kessler, Nick Trahearn, Benjamin Werner, Maria Vinci, Chris Jones, Andrea Sottoriva.
      Diffuse midline gliomas (DMGs) are highly aggressive, incurable childhood brain tumors. They present a clinical challenge due to many factors, including heterogeneity and diffuse infiltration, complicating disease management. Recent studies have described the existence of subclonal populations that may co-operate to drive pro-tumorigenic processes such as cellular invasion. However, a precise quantification of subclonal interactions is lacking, a problem that extends to other cancers. In this study, we combine spatial computational modeling of cellular interactions during invasion with co-evolution experiments of clonally disassembled patient-derived DMG cells. We design a Bayesian inference framework to quantify spatial subclonal interactions between molecular and phenotypically distinct lineages with different patterns of invasion. We show how this approach could discriminate genuine interactions, where one clone enhanced the invasive phenotype of another, from those apparently only due to the complex dynamics of spatially restricted growth. This study provides a framework for the quantification of subclonal interactions in DMG.
    Keywords:  CP: Cancer; DIPG; cancer; computational; cooperation; heterogeneity; interactions; mathematical; pediatric; subclonal
    DOI:  https://doi.org/10.1016/j.celrep.2022.111283
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