bims-malgli 2024-05-12 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–05–12
nine papers selected by
Oltea Sampetrean, Keio University

Editorial: Improving responses to immunotherapy in glioblastoma multiforme.
Glioma.
SMYD2 induced PGC1α methylation promotes stemness maintenance of glioblastoma stem cells.
CDKN2A/B homozygous deletion sensitizes IDH-mutant glioma to CDK4/6 inhibition.
A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives.
Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs.
Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma.
Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.
TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

Front Immunol. 2024 ;15 1407930

Editorial: Improving responses to immunotherapy in glioblastoma multiforme.

Stephanie E B McArdle, Divya Nagarajan, Michael E Barish.



Keywords:  future; glioblastoma multiforme (GBM); immunotherapy; improve; responses

DOI:  https://doi.org/10.3389/fimmu.2024.1407930
Nat Rev Dis Primers. 2024 May 09. 10(1): 33

Glioma.

Michael Weller, Patrick Y Wen, Susan M Chang, Linda Dirven, Michael Lim, Michelle Monje, Guido Reifenberger.

Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.

DOI: https://doi.org/10.1038/s41572-024-00516-y
Neuro Oncol. 2024 May 09. pii: noae090. [Epub ahead of print]

SMYD2 induced PGC1α methylation promotes stemness maintenance of glioblastoma stem cells.

Mengdie Li, Zhixiang Zhang, Liuguijie He, Xiefeng Wang, Jianxing Yin, Xiuxing Wang, Yongping You, Xu Qian, Xin Ge, Zhumei Shi.

   BACKGROUND: The high fatality rate of glioblastoma (GBM) is attributed to glioblastoma stem cells (GSCs), which exhibit heterogeneity and therapeutic resistance. Metabolic plasticity of mitochondria is the hallmark of GSCs. Targeting mitochondrial biogenesis of GSCs is crucial for improving clinical prognosis in GBM patients.
METHODS: SMYD2-induced PGC1α methylation and followed nuclear export is confirmed by co-immunoprecipitation, cellular fractionation, and immunofluorescence. The effects of SMYD2/PGC1α/CRM1 axis on GSCs mitochondrial biogenesis is validated by OCR, ECAR and intracranial glioma model.
RESULTS: PGC1α methylation causes disabled mitochondrial function to maintain the stemness, thereby enhancing radio-resistance of GSCs. SMYD2 drives PGC1α K224 methylation (K224me), which is essential for promoting the stem-like characteristics of GSCs. PGC1α K224me is preferred binding with CRM1, accelerating PGC1α nuclear export and subsequent dysfunction. Targeting PGC1α methylation exhibits significant radiotherapeutic efficacy and prolongs patient survival.
CONCLUSIONS: These findings unveil a novel regulatory pathway involving mitochondria that governs stemness in GSCs, thereby emphasizing promising therapeutic strategies targeting PGC1α and mitochondria for the treatment of GBM.

Keywords:  Glioblastoma; SMYD2/PGC1α/CRM1 axis; mitochondrial biogenesis; protein methylation; radiation resistance

DOI:  https://doi.org/10.1093/neuonc/noae090
Clin Cancer Res. 2024 May 08.

CDKN2A/B homozygous deletion sensitizes IDH-mutant glioma to CDK4/6 inhibition.

Ali M Nasser, Lisa Melamed, Ethan Wetzel, Chia-Chen Chang, Hiroaki Nagashima, Yosuke Kitagawa, Logan Muzyka, Hiroaki Wakimoto, Daniel P Cahill, Julie J Miller.

PURPOSE: Treatment paradigms for Isocitrate dehydrogenase (IDH) mutant gliomas are rapidly evolving. While typically indolent and responsive to initial treatment, these tumors invariably recur at higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcome. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi).
EXPERIMENTAL DESIGN: Cell viability, proliferation assays and flow cytometry were used to examine the pharmacologic effect of two distinct CDKis, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine efficacy and tolerability of CDKi in vivo.
RESULTS: CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models.
CONCLUSIONS: IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support investigation of the use of these agents in a clinical setting.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0562
Cells. 2024 Apr 23. pii: 726. [Epub ahead of print]13(9):

A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives.

Megan Montoya, Marco Gallus, Su Phyu, Jeffrey Haegelin, John de Groot, Hideho Okada.

  Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median overall survival of less than 2 years and a nearly 100% mortality rate under standard therapy that consists of surgery followed by combined radiochemotherapy. Therefore, new therapeutic strategies are urgently needed. The success of chimeric antigen receptor (CAR) T cells in hematological cancers has prompted preclinical and clinical investigations into CAR-T-cell treatment for GBM. However, recent trials have not demonstrated any major success. Here, we delineate existing challenges impeding the effectiveness of CAR-T-cell therapy for GBM, encompassing the cold (immunosuppressive) microenvironment, tumor heterogeneity, T-cell exhaustion, local and systemic immunosuppression, and the immune privilege inherent to the central nervous system (CNS) parenchyma. Additionally, we deliberate on the progress made in developing next-generation CAR-T cells and novel innovative approaches, such as low-intensity pulsed focused ultrasound, aimed at surmounting current roadblocks in GBM CAR-T-cell therapy.

Keywords:  CAR-T-cell therapy; glioblastoma; tumor immune microenvironment

DOI:  https://doi.org/10.3390/cells13090726
Nat Commun. 2024 May 09. 15(1): 3905

Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs.

Ting Xie, Adi Danieli-Mackay, Mariachiara Buccarelli, Mariano Barbieri, Ioanna Papadionysiou, Q Giorgio D'Alessandris, Claudia Robens, Nadine Übelmesser, Omkar Suhas Vinchure, Liverana Lauretti, Giorgio Fotia, Roland F Schwarz, Xiaotao Wang, Lucia Ricci-Vitiani, Jay Gopalakrishnan, Roberto Pallini, Argyris Papantonis.

Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compile a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generate and analyze 5 kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map thousands of standalone and complex structural variants (SVs) and the multitude of neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can relate to patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.

DOI: https://doi.org/10.1038/s41467-024-48053-2
bioRxiv. 2024 Apr 27. pii: 2024.04.24.590852. [Epub ahead of print]

Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma.

Y Licón-Muñoz, V Avalos, S Subramanian, B Granger, F Martinez, S Varela, D Moore, E Perkins, M Kogan, S Berto, M O Chohan, C A Bowers, S G M Piccirillo.

The sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and emergence of recurrence. Here, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass (T_Mass) and the SVZ (T_SVZ) of 15 GBM patients and 2 histologically normal SVZ (N_SVZ) samples as controls. We identified a mesenchymal signature in the T_SVZ of GBM patients: tumor cells from the T_SVZ relied on the ZEB1 regulatory network, whereas tumor cells in the T_Mass relied on the TEAD1 regulatory network. Moreover, the T_SVZ microenvironment was predominantly characterized by tumor-supportive microglia, which spatially co-exist and establish heterotypic interactions with tumor cells. Lastly, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays revealed that the IL-1β/IL-1RAcP and Wnt-5a/Frizzled-3 pathways are therapeutic targets in the T_SVZ microenvironment. Our data provide insights into the biology of the SVZ in GBM patients and identify specific targets of this microenvironment.

DOI: https://doi.org/10.1101/2024.04.24.590852
Neuro Oncol. 2024 May 08. pii: noae080. [Epub ahead of print]

Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.

Gunther Nussbaumer, Martin Benesch, Yura Grabovska, Alan Mackay, David Castel, Jacques Grill, Marta M Alonso, Manila Antonelli, Simon Bailey, Joshua N Baugh, Veronica Biassoni, Mirjam Blattner Johnson, Alberto Broniscer, Andrea Carai, Giovanna Stefania Colafati, Niclas Colditz, Selim Corbacioglu, Shauna Crampsie, Natacha Entz-Werle, Matthias Eyrich, Lea L Friker, Michael C Frühwald, Maria Luisa Garrè, Nicolas U Gerber, Felice Giangaspero, Maria J Gil-da-Costa, Norbert Graf, Darren Hargrave, Peter Hauser, Ulrich Herrlinger, Marion Hoffmann, Esther Hulleman, Elisa Izquierdo, Sandra Jacobs, Michael Karremann, Antonis Kattamis, Rejin Kebudi, Rolf-Dieter Kortmann, Robert Kwiecien, Maura Massimino, Angela Mastronuzzi, Evelina Miele, Giovanni Morana, Claudia M Noack, Virve Pentikainen, Thomas Perwein, Stefan M Pfister, Torsten Pietsch, Kleoniki Roka, Sabrina Rossi, Stefan Rutkowski, Elisabetta Schiavello, Clemens Seidel, Jaroslav Štěrba, Dominik Sturm, David Sumerauer, Anna Tacke, Sara Temelso, Chiara Valentini, Dannis van Vuurden, Pascale Varlet, Sophie E M Veldhuijzen van Zanten, Maria Vinci, André O von Bueren, Monika Warmuth-Metz, Pieter Wesseling, Maria Wiese, Johannes E A Wolff, Josef Zamecnik, Andrés Morales La Madrid, Brigitte Bison, Gerrit H Gielen, David T W Jones, Chris Jones, Christof M Kramm.

   BACKGROUND: The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet.
METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization.
RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS.
CONCLUSION: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

Keywords:  H3-wildtype and IDH-wildtype; Pediatric-type glioma; chromosome 6; gliomatosis cerebri; pedHGG_RTK2; pediatric-type high-grade glioma

DOI:  https://doi.org/10.1093/neuonc/noae080
Nat Commun. 2024 May 08. 15(1): 3882

TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

Richard G Everson, Willy Hugo, Lu Sun, Joseph Antonios, Alexander Lee, Lizhong Ding, Melissa Bu, Sarah Khattab, Carolina Chavez, Emma Billingslea-Yoon, Andres Salazar, Benjamin M Ellingson, Timothy F Cloughesy, Linda M Liau, Robert M Prins.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

DOI: https://doi.org/10.1038/s41467-024-48073-y