bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–08–25
eight papers selected by
Oltea Sampetrean, Keio University
  1. Urinary D-asparagine level is decreased by the presence of glioblastoma.
  2. Navigating glioblastoma complexity: the interplay of neurotransmitters and chromatin.
  3. Contemporary Prognostic Signatures and Refined Risk Stratification of Gliomas: An Analysis of 4,400 Tumors.
  4. Hypoxia-induced complement component 3 promotes aggressive tumor growth in the glioblastoma microenvironment.
  5. Mapping Tumor Habitats in IDH-Wild Type Glioblastoma: Integrating MR Imaging, Pathologic, and RNA Data from Ivy Glioblastoma Atlas Project.
  6. CD58 defines regulatory macrophages within the tumor microenvironment.
  7. Clinical utility of a blood based assay for the detection of IDH1.R132H-mutant gliomas.
  8. Excessive lipid production shapes glioma tumor microenvironment.
  1. Acta Neuropathol Commun. 2024 Aug 20. 12(1): 122
    Urinary D-asparagine level is decreased by the presence of glioblastoma.
    Yusuke Nakade, Masashi Kinoshita, Mitsutoshi Nakada, Hemragul Sabit, Toshiya Ichinose, Masashi Mita, Takeo Yuno, Moeko Noguchi-Shinohara, Kenjiro Ono, Yasunori Iwata, Takashi Wada.
      Gliomas, particularly glioblastomas (GBMs), pose significant challenges due to their aggressiveness and poor prognosis. Early detection through biomarkers is critical for improving outcomes. This study aimed to identify novel biomarkers for gliomas, particularly GBMs, using chiral amino acid profiling. We used chiral amino acid analysis to measure amino acid L- and D-isomer levels in resected tissues (tumor and non-tumor), blood, and urine from 33 patients with primary gliomas and 24 healthy volunteers. The levels of D-amino acid oxidase (DAO), a D-amino acid-degrading enzyme, were evaluated to investigate the D-amino acid metabolism in brain tissue. The GBM mouse model was created by transplanting GBM cells into the brain to confirm whether gliomas affect blood and urine chiral amino acid profiles. We also assessed whether D-amino acids produced by GBM cells are involved in cell proliferation. D-asparagine (D-Asn) levels were higher and DAO expression was lower in glioma than in non-glioma tissues. Blood and urinary D-Asn levels were lower in patients with GBM than in healthy volunteers (p < 0.001), increasing after GBM removal (p < 0.05). Urinary D-Asn levels differentiated between healthy volunteers and patients with GBM (area under the curve: 0.93, sensitivity: 0.88, specificity: 0.92). GBM mouse model validated the decrease of urinary D-Asn in GBM. GBM cells used D-Asn for cell proliferation. Gliomas induce alterations in chiral amino acid profiles, affecting blood and urine levels. Urinary D-Asn emerges as a promising diagnostic biomarker for gliomas, reflecting tumor presence and severity.
    Keywords:  Biomarker; Chiral amino acids; D-amino acids; Glioblastoma; Glioma; Urine
    DOI:  https://doi.org/10.1186/s40478-024-01836-6
  2. Mol Biol Rep. 2024 Aug 17. 51(1): 912
    Navigating glioblastoma complexity: the interplay of neurotransmitters and chromatin.
    Jessica Romero-Reyes, Edgar Ricardo Vázquez-Martínez, Carlos-Camilo Silva, Anayansi Molina-Hernández, Néstor Fabián Díaz, Ignacio Camacho-Arroyo.
      Glioblastoma is the most aggressive brain cancer with an unfavorable prognosis for patient survival. Glioma stem cells, a subpopulation of cancer cells, drive tumor initiation, self-renewal, and resistance to therapy and, together with the microenvironment, play a crucial role in glioblastoma maintenance and progression. Neurotransmitters such as noradrenaline, dopamine, and serotonin have contrasting effects on glioblastoma development, stimulating or inhibiting its progression depending on the cellular context and through their action on glioma stem cells, perhaps changing the epigenetic landscape. Recent studies have revealed that serotonin and dopamine induce chromatin modifications related to transcriptional plasticity in the mammalian brain and possibly in glioblastoma; however, this topic still needs to be explored because of its potential implications for glioblastoma treatment. Also, it is essential to consider that neurotransmitters' effects depend on the tumor's microenvironment since it can significantly influence the response and behavior of cancer cells. This review examines the possible role of neurotransmitters as regulators of glioblastoma development, focusing on their impact on the chromatin of glioma stem cells.
    Keywords:  Glioblastoma; Glioma stem cells; Neurotransmitters; Post-translational modifications; Serotonylation
    DOI:  https://doi.org/10.1007/s11033-024-09853-3
  3. Neuro Oncol. 2024 Aug 21. pii: noae164. [Epub ahead of print]
    Contemporary Prognostic Signatures and Refined Risk Stratification of Gliomas: An Analysis of 4,400 Tumors.
    Hia S Ghosh, Ruchit V Patel, Eleanor Woodward, Noah F Greenwald, Varun M Bhave, Eduardo A Maury, Gregory Cello, Samantha E Hoffman, Yvonne Li, Hersh Gupta, Gilbert Youssef, Liam F Spurr, Jayne Vogelzang, Mehdi Touat, Frank Dubois, Andrew D Cherniack, Xiaopeng Guo, Sherwin Tavakol, Gino Cioffi, Neal I Lindeman, Azra H Ligon, E Antonio Chiocca, David A Reardon, Patrick Y Wen, David Meredith, Sandro Santagata, Jill S Barnholtz-Sloan, Keith L Ligon, Rameen Beroukhim, Wenya Linda Bi.
       BACKGROUND: With the significant shift in the classification, risk stratification, and standards of care for gliomas, we sought to understand how the overall survival of patients with these tumors is impacted by molecular features, clinical metrics, and treatment received.
    METHODS: We assembled a cohort of patients with a histopathologically diagnosed glioma from The Cancer Genome Atlas, Project Genomics Evidence Neoplasia Information Exchange, and Dana-Farber Cancer Institute/Brigham and Women's Hospital. This incorporated retrospective clinical, histological, and molecular data alongside prospective assessment of patient survival.
    RESULTS: 4,400 gliomas were identified: 2,195 glioblastoma, 1,198 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, 271 other IDH1/2-wildtype glioma, and 205 pediatric-type glioma. Molecular classification updated 27.2% of gliomas from their original histopathologic diagnosis. Examining the distribution of molecular alterations across glioma subtypes revealed mutually exclusive alterations within tumorigenic pathways. Non-TCGA patients had significantly improved overall survival compared to TCGA patients, with 26.7%, 55.6%, and 127.8% longer survival for glioblastoma, IDH1/2-mutant astrocytoma, and oligodendroglioma respectively (all p<0.01). Several prognostic features were characterized, including NF1 alteration and 21q loss in glioblastoma, and EGFR amplification and 22q loss in IDH1/2-mutant astrocytoma. Leveraging the size of this cohort, nomograms were generated to assess the probability of overall survival based on patient age, the molecular features of a tumor, and the treatment received.
    CONCLUSIONS: By applying modern molecular criteria, we characterize the genomic diversity across glioma subtypes, identify clinically applicable prognostic features, and provide a contemporary update on patient survival to serve as a reference for ongoing investigations.
    Keywords:  astrocytoma; glioma; molecular classification; oligodendroglioma; prognosis
    DOI:  https://doi.org/10.1093/neuonc/noae164
  4. JCI Insight. 2024 Aug 22. pii: e179854. [Epub ahead of print]
    Hypoxia-induced complement component 3 promotes aggressive tumor growth in the glioblastoma microenvironment.
    Rebecca Rosberg, Karolina I Smolag, Jonas Sjölund, Elinn Johansson, Christina Bergelin, Julia Wahldén, Vasiliki Pantazopoulou, Crister Ceberg, Kristian Pietras, Anna M Blom, Alexander Pietras.
      Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single cell, and spatially resolved transcriptomic data from human GBM patients. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level-dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. C3a induced M2 polarization of cultured microglia and macrophages in a C3aR-dependent fashion. Targeting C3aR using the antagonist SB290157 prolonged survival of glioma bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM, and support a role of hypoxia-induced C3a-C3aR signaling as a contributor to glioma aggressiveness by regulating macrophage polarization.
    Keywords:  Cancer; Complement; Hypoxia; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.179854
  5. Neuro Oncol. 2024 Aug 23. pii: noae161. [Epub ahead of print]
    Mapping Tumor Habitats in IDH-Wild Type Glioblastoma: Integrating MR Imaging, Pathologic, and RNA Data from Ivy Glioblastoma Atlas Project.
    Ji Eun Park, Joo Young Oh, Do Hoon Park, Ho-Su Lee, Shinkyo Yoon, Nak Young Kim, Seo Young Park, Sang Woo Song, Young-Hoon Kim, Chang-Ki Hong, Jeong Hoon Kim, Ho Sung Kim.
       BACKGROUND: To spatially validate intratumoral subregions (tumor habitat) using physiologic MRI on pathology of the isocitrate dehydrogenase (IDH)-wildtype whole-glioblastoma sample.
    METHODS: Data of 20 patients (168 slides) were obtained from the Ivy Glioblastoma Atlas Project. On MRI, tumor habitats were defined using voxel-wise clustering of apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps for contrast-enhancing lesion (CEL) and non-enhancing lesion (NEL). On pathology slides, normalized areas of leading edge (LE), infiltrating tumor (IT), cellular tumor (CT), hypervascular lesion (CThypervascular), and perinecrotic lesion (CTperinecrotic) were obtained. Gross specimen was co-registered on MRI and correlation between pathology-MRI habitats was calculated. RNA sequencing of 67 samples was assessed using 4 Neftel subtypes and further correlated with pathology.
    RESULTS: Six tumor habitats were identified: hypervascular, hypovascular cellular, and hypovascular hypocellular habitats for CEL and NEL. CT was correlated with hypovascular cellular habitat in CEL (r= 0.238, p =.005). IT was correlated with hypovascular cellular habitat in NEL (r= 0.294, p =.017). CThypervascular was correlated with hypervascular habitat in NEL (r= 0.195, p = .023). CTperinecrotic was correlated with imaging necrosis (r= 0.199, p =.005). Astrocyte-like subtypes were correlated with IT (r= 0.256, p <.001), while mesenchymal-like subtypes were correlated with CTperinecrotic area (r= 0.246, p <.001).
    CONCLUSION: Pathologically matched tumor subregions were cellular tumor with hypovascular cellular habitat in CEL and infiltrative tumor with hypovascular cellular habitat in NEL. Identification of the most aggressive as well as infiltrative tumor portion can be achieved using non-invasive MRI tumor habitats.
    Keywords:  MRI; glioblastoma; pathology; tumor subregions; validation
    DOI:  https://doi.org/10.1093/neuonc/noae161
  6. Commun Biol. 2024 Aug 21. 7(1): 1025
    CD58 defines regulatory macrophages within the tumor microenvironment.
    Bo Wu, Xiaoni Zhan, Meixi Jiang.
      CD58 has been implicated in immune suppression and is associated with stemness in various types of cancer. Nonetheless, efficient biomarkers for assessing cancer patient response to immunotherapy are lacking. The present work focused on assessing the immune predictive significance of CD58 for patients with glioma. The expression of CD58 correlates with the clinicopathologic characteristics of patients with glioma, suggesting CD58high cells to signify glioma with tumorigenic potential. The CD58high cells displayed accelerated tumor formation compared to CD58low cells in vivo. Taken together, CD58 could potentially serve as a marker for glioma. CD58high glioma induces macrophage polarization through CXCL5 secretion, where M2 macrophages regulate PD-L1 expression within CD58high glioma via IL-6 production in vitro. Moreover, it was found that combination treatment with CD58 significantly increased the volume of tumors in the xenograft specimens. Evaluating CD58 expression represents a promising approach for identifying patients who can benefit from immunotherapy.
    DOI:  https://doi.org/10.1038/s42003-024-06712-6
  7. Nat Commun. 2024 Aug 16. 15(1): 7074
    Clinical utility of a blood based assay for the detection of IDH1.R132H-mutant gliomas.
    Syeda Maheen Batool, Ana K Escobedo, Tiffaney Hsia, Emil Ekanayake, Sirena K Khanna, Austin S Gamblin, Hui Zheng, Johan Skog, Julie J Miller, Anat O Stemmer-Rachamimov, Daniel P Cahill, Leonora Balaj, Bob S Carter.
      Glioma represents the most common central nervous system neoplasm in adults. Current classification scheme utilizes molecular alterations, particularly IDH1.R132H, to stratify lesions into distinct prognostic groups. Identification of the single nucleotide variant through traditional tissue biopsy assessment poses procedural risks and does not fully reflect the heterogeneous and evolving tumor landscape. Here, we introduce a liquid biopsy assay, mt-IDH1dx. The blood-based test allows minimally invasive detection of tumor-derived extracellular vesicle RNA using only 2 ml plasma volume. We perform rigorous, blinded validation testing across the study population (n = 133), comprising of IDH1.R132H patients (n = 80), IDH1 wild-type gliomas (n = 44), and age matched healthy controls (n = 9). Results from our plasma testing demonstrate an overall sensitivity of 75.0% (95% CI: 64.1%-84.0%), specificity 88.7% (95% CI: 77.0%-95.7%), positive predictive value 90.9%, and negative predictive value 70.1% compared to the tissue gold standard. In addition to fundamental diagnostic applications, the study also highlights the utility of mt-IDH1dx platform for blood-based monitoring and surveillance, offering valuable prognostic information. Finally, the optimized workflow enables rapid and efficient completion of both tumor tissue and plasma testing in under 4 hours from the time of sampling.
    DOI:  https://doi.org/10.1038/s41467-024-51332-7
  8. Ultrastruct Pathol. 2024 Aug 19. 1-11
    Excessive lipid production shapes glioma tumor microenvironment.
    Haitham H Maraqah, John Paul Aboubechara, Mones S Abu-Asab, Han Sung Lee, Orwa Aboud.
      Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.
    Keywords:  Astrocytoma; glioblastoma; glycolysis; immune evasion; lipid accumulation; mitochondrial dysfunction; oxidative phosphorylation; therapeutic strategies; tumor microenvironment; ultrastructural analysis
    DOI:  https://doi.org/10.1080/01913123.2024.2392728
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