bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒06‒19
thirteen papers selected by
Oltea Sampetrean
Keio University

  1. Sci Rep. 2022 Jun 14. 12(1): 9838
      Glioblastoma is a highly aggressive brain tumor with poor patient prognosis. Treatment outcomes remain limited, partly due to intratumoral heterogeneity and the invasive nature of the tumors. Glioblastoma cells invade and spread into the surrounding brain tissue, and even between hemispheres, thus hampering complete surgical resection. This invasive motility can arise through altered properties of the cytoskeleton. We hypothesize that cytoskeletal organization and dynamics can provide important clues to the different malignant states of glioblastoma. In this study, we investigated cytoskeletal organization in glioblastoma cells with different subtype expression profiles, and cytoskeletal dynamics upon subtype transitions. Analysis of the morphological, migratory, and invasive properties of glioblastoma cells identified cytoskeletal components as phenotypic markers that can serve as diagnostic or prognostic tools. We also show that the cytoskeletal function and malignant properties of glioblastoma cells shift during subtype transitions induced by altered expression of the neurodevelopmental transcription factor SOX2. The potential of SOX2 re-expression to reverse the mesenchymal subtype into a more proneural subtype might open up strategies for novel glioblastoma treatments.
  2. Front Cell Dev Biol. 2022 ;10 835273
      We have observed a drug-tolerant/persister state in a human glioblastoma (GBM) cell line after exposure to temozolomide, the standard-of-care chemotherapeutic agent for GBM. We used a multicolor lentiviral genetic barcode labeling to follow cell population evolution during temozolomide treatment. We observed no change in the distribution of the different colored populations of cells in persister or resistant cells suggesting that pre-existing minor subpopulations, which would be expected to be restricted to a single color, were not amplified/selected during the response to the drug. We have previously identified four genes (CHI3L1, FAT2, KLK5, and HB-EGF) that were over-expressed during the persister stage. Single-cell analysis of these four genes indicated that they were expressed in different individual cells ruling out the existence of a single persister-specific clone but suggesting rather a global answer. Even so, the transitory silencing of CHI3L1, FAT2, or KLK5 influenced the expression of the other three genes and the survival of U251 cells in absence of temozolomide. Since proteins encoded by the four genes are all localized in the extracellular matrix or interact within the extracellular compartment, we propose that cellular interactions and communications are important during the persister stage before the acquisition of chemo-resistance. Thus, persisters might be a new therapeutically relevant target in GBM.
    Keywords:  barcoding; clones; glioma; persisters; resistance
  3. J Neurooncol. 2022 Jun 14.
      PURPOSE: The presence of necrosis or microvascular proliferation was previously the hallmark for glioblastoma (GBM) diagnosis. The 2021 WHO classification now considers IDH-wildtype diffuse astrocytic tumors without the histological features of glioblastoma (that would have otherwise been classified as grade 2 or 3) as molecular GBM (molGBM) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/-10 copy changes. We hypothesize that these tumors are early histological GBM and will eventually develop the classic histological features.METHODS: Medical records from 65 consecutive patients diagnosed with molGBM at three tertiary-care centers from our institution were retrospectively reviewed from November 2017-October 2021. Only patients who underwent reoperation for tumor recurrence and whose tissue at initial diagnosis and recurrence was available were included in this study. The detailed clinical, histopathological, and radiographic scenarios are presented.
    RESULTS: Five patients were included in our final cohort. Three (60%) patients underwent reoperation for recurrence in the primary site and 2 (40%) underwent reoperation for distal recurrence. Microvascular proliferation and pseudopalisading necrosis were absent at initial diagnosis but present at recurrence in 4 (80%) patients. Radiographically, all tumors showed contrast enhancement, however none of them showed the classic radiographic features of GBM at initial diagnosis.
    CONCLUSIONS: In this manuscript we present preliminary data for a hypothesis that molGBMs are early histological GBMs diagnosed early in their natural history of disease and will eventually develop necrosis and microvascular proliferation. Further correlative studies are needed in support of this hypothesis.
    Keywords:  Diffuse astrocytic glioma; Diffuse astrocytoma; Glioma; Overall survival; Progression-free survival
  4. Commun Biol. 2022 Jun 16. 5(1): 593
      The heterogeneity of glioblastoma multiforme (GBM) leads to poor patient prognosis. Here, we aim to investigate the mechanism through which GBM heterogeneity is coordinated to promote tumor progression. We find that proneural (PN)-GBM stem cells (GSCs) secreted dopamine (DA) and transferrin (TF), inducing the proliferation of mesenchymal (MES)-GSCs and enhancing their susceptibility toward ferroptosis. PN-GSC-derived TF stimulates MES-GSC proliferation in an iron-dependent manner. DA acts in an autocrine on PN-GSC growth in a DA receptor D1-dependent manner, while in a paracrine it induces TF receptor 1 expression in MES-GSCs to assist iron uptake and thus enhance ferroptotic vulnerability. Analysis of public datasets reveals worse prognosis of patients with heterogeneous GBM with high iron uptake than those with other GBM subtypes. Collectively, the findings here provide evidence of commensalism symbiosis that causes MES-GSCs to become iron-addicted, which in turn provides a rationale for targeting ferroptosis to treat resistant MES GBM.
  5. Pharmacol Res. 2022 Jun 14. pii: S1043-6618(22)00253-5. [Epub ahead of print] 106308
      This review describes recent technological advances applied to glioblastoma (GBM), a brain tumor with dismal prognosis. International consortial efforts suggest the presence of molecular subtypes within histologically identical GBM tumors. This emphasizes that future treatment decisions should no longer be made based solely on morphological analyses, but must now take into consideration such molecular and cellular heterogeneity. The use of single-cell technologies has advanced our understanding and assignation of functional subtypes revealing therapeutic vulnerabilities. Our team has developed stratification approaches in the past few years, and we have been able to identify patient cohorts enriched for various signaling pathways. Importantly, our Glioportal brain tumor resource has been established under the National Neuroscience Institute Tissue Bank in 2021. This resource offers preclinical capability to validate working hypotheses established from patient clinical datasets. This review highlights recent developments with the ultimate goal of assigning functional meaning to molecular subtypes, revealing therapeutic vulnerabilities.
    Keywords:  glioblastoma; molecular subtypes; multi-comics; patient, stratification; precision medicine; single-cell technology
  6. World Neurosurg. 2022 Jun 10. pii: S1878-8750(22)00803-8. [Epub ahead of print]
      OBJECTIVE: To summarize the clinical characteristics, histo-genomic profiles, management strategies, and survival outcomes of H3K27M-altered adult diffuse midline gliomas (aDMGs).METHODS: PubMed, Scopus, and Cochrane databases were used to identify relevant articles. Papers including H3K27M-altered aDMGs with sufficient clinical outcome data were included. Descriptive clinical characteristics and survival analysis were also conducted.
    RESULTS: Twenty studies describing 135 patients were included. The median age at diagnosis was 42 years and there was a slight male predominance (N=60, 54%). In our cohort, fifteen (11%) patients experienced headache, 10 had nausea and vomiting (7%), and 10 had ataxia (7%). Within this cohort, histopathologic diagnoses included glioblastoma (N=22, 40%) and anaplastic astrocytoma (N=21, 38%), while genetic alterations included ATRX mutation (N=22, 16%), PTPN11 mutation (N=9, 7%), and MGMT promoter methylation (N=9, 7%). Among histo-genetic alterations, only ATRX mutation was associated with survival and correlated with worse prognosis (Log-risk, P=0.04). Neither surgical resection versus biopsy nor greater extent of resection demonstrated survival benefit in our cohort. Chemotherapy was administered in 98 (73%) cases with radiotherapy administered in 71 (53%) cases. Unlike chemotherapy, radiotherapy demonstrated a significant survival benefit (log-risk, P=0.019). Median overall survival (OS) and progression-free survival within our patient cohort were 10 and 7 months, respectively.
    CONCLUSION: H3K27M-altered aDMGs were associated with relatively poor survival. ATRX gene mutation was significantly associated with survival disadvantage, while radiotherapy was associated with survival benefit. Large, prospective studies are needed to establish a standard management strategy and provide reliable prognostic conclusions.
    Keywords:  Gliomas; H3K27M; brain cancer; brain tumors; diffuse midline gliomas
  7. Nucleic Acids Res. 2022 Jun 13. pii: gkac485. [Epub ahead of print]
      Gliomas are one of the most common and lethal brain tumors among adults. One process that contributes to glioma progression and recurrence is the epithelial to mesenchymal transition (EMT). EMT is regulated by a set of defined transcription factors which tightly regulate this process, among them is the basic helix-loop-helix family member, TWIST1. Here we show that TWIST1 is methylated on lysine-33 at chromatin by SETD6, a methyltransferase with expression levels correlating with poor survival in glioma patients. RNA-seq analysis in U251 glioma cells suggested that both SETD6 and TWIST1 regulate cell adhesion and migration processes. We further show that TWIST1 methylation attenuates the expression of the long-non-coding RNA, LINC-PINT, thereby promoting EMT in glioma. Mechanistically, TWIST1 methylation represses the transcription of LINC-PINT by increasing the occupancy of EZH2 and the catalysis of the repressive H3K27me3 mark at the LINC-PINT locus. Under un-methylated conditions, TWIST1 dissociates from the LINC-PINT locus, allowing the expression of LINC-PINT which leads to increased cell adhesion and decreased cell migration. Together, our findings unravel a new mechanistic dimension for selective expression of LINC-PINT mediated by TWIST1 methylation.
  8. J Hematol Oncol. 2022 Jun 11. 15(1): 80
      Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease-switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy-which utilizes strategies to reenergize or alter the immune system to target cancer-have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-β signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice.
    Keywords:  CAR-T cells; Dendritic cell vaccines; Glioblastoma; Immune checkpoint inhibitors; Immuno-oncology; Immunotherapy; Peptide vaccines; Tumor microenvironment
  9. Neuro Oncol. 2022 Jun 18. pii: noac154. [Epub ahead of print]
      BACKGROUND: Lower grade gliomas (LGG) are heterogenous diseases by clinical, histological, and molecular criteria. We aimed to personalize the diagnosis and therapy of LGG patients by developing and validating robust cellular morphometric subtypes (CMS) and to uncover the molecular signatures underlying these subtypes.METHODS: Cellular morphometric biomarkers (CMBs) were identified with artificial intelligence technique from TCGA-LGG cohort. Consensus clustering was used to define CMS. Survival analysis was performed to assess the clinical impact of CMBs and CMS. A nomogram was constructed to predict 3- and 5- year overall survival (OS) of LGG patients. Tumor mutational burden (TMB), and immune cell infiltration between subtypes were analyzed using the Mann-Whitney test. The double-blinded validation for important immunotherapy-related biomarkers were executed using immunohistochemistry (IHC).
    RESULTS: We developed a machine learning pipeline to extract CMBs from whole slide images of tissue histology; identifying and externally validating robust CMS of LGGs in multi-center cohorts. The subtypes had independent predicted OS across all three independent cohorts. In the TCGA-LGG cohort, patients within the poor-prognosis subtype responded poorly to primary and follow-up therapies. LGGs within the poor-prognosis subtype were characterized by high mutational burden, high frequencies of copy number alterations, and high levels of tumor-infiltrating lymphocytes and immune checkpoint genes. Higher levels of PD-1/PD-L1/CTLA-4 were confirmed by immunohistochemical staining. In addition, the subtypes learned from LGG demonstrates translational impact on glioblastoma (GBM).
    CONCLUSIONS: We developed and validated a framework (CMS-ML) for CMS discovery in LGG associated with specific molecular alterations, immune micro-environment, prognosis, and treatment response.
    Keywords:  Stacked Predictive Sparse Decomposition; cellular morphometric biomarkers; cellular morphometric subtypes; glioblastoma; immunohistochemistry; lower grade glioma; nomogram; overall survival
  10. Cancer Cell. 2022 Jun 13. pii: S1535-6108(22)00220-3. [Epub ahead of print]40(6): 639-655.e13
      Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas by spatially resolved transcriptomics, metabolomics, and proteomics. By deciphering regionally shared transcriptional programs across patients, we infer that glioblastoma is organized by spatial segregation of lineage states and adapts to inflammatory and/or metabolic stimuli, reminiscent of the reactive transformation in mature astrocytes. Integration of metabolic imaging and imaging mass cytometry uncovered locoregional tumor-host interdependence, resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-number alterations emphasizes a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments.
    Keywords:  MALDI; genomic instability; glioblastoma heterogeneity; imaging mass cytometry; microenvironment; multiomics; spatially resolved transcriptomics; tumor ecosystem
  11. Nat Rev Cancer. 2022 Jun 16.
      Malignant brain tumours are complex ecosystems containing neoplastic and stromal components that generate adaptive and evolutionarily driven aberrant tissues in the central nervous system. Brain cancers are cultivated by a dynamic population of stem-like cells that enforce intratumoural heterogeneity and respond to intrinsic microenvironment or therapeutically guided insults through proliferation, plasticity and restructuring of neoplastic and stromal components. Far from a rigid hierarchy, heterogeneous neoplastic populations transition between cellular states with differential self-renewal capacities, endowing them with powerful resilience. Here we review the biological machinery used by brain tumour stem cells to commandeer tissues in the intracranial space, evade immune responses and resist chemoradiotherapy. Through recent advances in single-cell sequencing, improved models to investigate the role of the tumour microenvironment and a deeper understanding of the fundamental role of the immune system in cancer biology, we are now better equipped to explore mechanisms by which these processes can be exploited for therapeutic benefit.