bims-malgli 2024-06-02 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2024–06–02
nine papers selected by
Oltea Sampetrean, Keio University

Chromothripsis is rare in IDH-mutant gliomas compared to IDH-wild-type glioblastomas whereas whole-genome duplication is equally frequent in both tumor types.
Glioblastoma microenvironment-from biology to therapy.
Radiation-Induced Cellular Plasticity: A Strategy for Combatting Glioblastoma.
Spatial analysis of recurrent glioblastoma reveals perivascular niche organization.
L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial.
Rapid detection of IDH mutations in gliomas by intraoperative mass spectrometry.
Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy.
Protocol to quantify immune cell distribution from the vasculature to the glioma microenvironment on sequential immunofluorescence multiplex images.
Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales.

Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae059

Chromothripsis is rare in IDH-mutant gliomas compared to IDH-wild-type glioblastomas whereas whole-genome duplication is equally frequent in both tumor types.

Baptiste Sourty, Laëtitia Basset, Alix Fontaine, Emmanuel Garcion, Audrey Rousseau.

   Background: Adult-type diffuse gliomas comprise IDH (isocitrate dehydrogenase)-mutant astrocytomas, IDH-mutant 1p/19q-codeleted oligodendrogliomas (ODG), and IDH-wild-type glioblastomas (GBM). GBM displays genome instability, which may result from 2 genetic events leading to massive chromosome alterations: Chromothripsis (CT) and whole-genome duplication (WGD). These events are scarcely described in IDH-mutant gliomas. The better prognosis of the latter may be related to their genome stability compared to GBM.
Methods: Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using the Kaplan-Meier method.
Results: At initial diagnosis, 37 GBM (18.7%) displayed CT versus 5 IDH-mutant gliomas (4.7%; P = .0008), the latter were all high-grade (grade 3 or 4) astrocytomas. WGD was detected at initial diagnosis in 18 GBM (9.3%) and 9 IDH-mutant gliomas (5 astrocytomas and 4 oligodendrogliomas, either low- or high-grade; 8.5%). Neither CT nor WGD was associated with overall survival in GBM or in IDH-mutant gliomas.
Conclusions: CT is less frequent in IDH-mutant gliomas compared to GBM. The absence of CT in ODG and grade 2 astrocytomas might, in part, explain their genome stability and better prognosis, while CT might underlie aggressive biological behavior in some high-grade astrocytomas. WGD is a rare and early event occurring equally in IDH-mutant gliomas and GBM.

Keywords:  IDH-mutant glioma; chromothripsis; genome instability; glioblastoma; whole-genome duplication

DOI:  https://doi.org/10.1093/noajnl/vdae059
Genes Dev. 2024 May 29.

Glioblastoma microenvironment-from biology to therapy.

Renee D Read, Zoe M Tapp, Prajwal Rajappa, Dolores Hambardzumyan.

  Glioblastoma (GBM) is the most aggressive primary brain cancer. These tumors exhibit high intertumoral and intratumoral heterogeneity in neoplastic and nonneoplastic compartments, low lymphocyte infiltration, and high abundance of myeloid subsets that together create a highly protumorigenic immunosuppressive microenvironment. Moreover, heterogeneous GBM cells infiltrate adjacent brain tissue, remodeling the neural microenvironment to foster tumor electrochemical coupling with neurons and metabolic coupling with nonneoplastic astrocytes, thereby driving growth. Here, we review heterogeneity in the GBM microenvironment and its role in low-to-high-grade glioma transition, concluding with a discussion of the challenges of therapeutically targeting the tumor microenvironment and outlining future research opportunities.

Keywords:  glial cells; glioblastoma; glioma stem cell; lymphoid cells; myeloid cells; stem cell niche; tumor microenvironment

DOI:  https://doi.org/10.1101/gad.351427.123
bioRxiv. 2024 May 16. pii: 2024.05.13.593985. [Epub ahead of print]

Radiation-Induced Cellular Plasticity: A Strategy for Combatting Glioblastoma.

Ling He, Daria Azizad, Kruttika Bhat, Angeliki Ioannidis, Carter J Hoffmann, Evelyn Arambula, Aparna Bhaduri, Harley I Kornblum, Frank Pajonk.

Glioblastoma is the deadliest brain cancer in adults and almost all patients succumb to the tumor. While surgery followed by chemo-radiotherapy significantly delays disease progression, these treatments do not lead to long-term tumor control and targeted therapies or biologics have so far failed to further improve survival. Utilizing a transient radiation-induced state of multipotency we used the adenylcyclase activator forskolin to alter the cellular fate of glioma cells in response to radiation. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation and led to a distinct gene expression profile. scRNAseq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotypes. In vivo this treatment led to a loss of glioma stem cells and prolonged median survival in mouse models of glioblastoma. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.

DOI: https://doi.org/10.1101/2024.05.13.593985
JCI Insight. 2024 May 23. pii: e179853. [Epub ahead of print]

Spatial analysis of recurrent glioblastoma reveals perivascular niche organization.

Ugoma Onubogu, Chandler D Gatenbee, Sandhya Prabhakaran, Kelsey Wolfe, Benjamin Oakes, Roberto Salatino, Rachael Vaubel, Oszkar Szentirmai, Alexander R A Anderson, Michalina Janiszewska.

  Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the extracellular matrix (ECM), identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages. Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight novel genetic and spatial dependencies.

Keywords:  Brain cancer; Macrophages; Molecular pathology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.179853
Nat Commun. 2024 May 28. 15(1): 4210

L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial.

Frank A Giordano, Julian P Layer, Sonia Leonardelli, Lea L Friker, Roberta Turiello, Dillon Corvino, Thomas Zeyen, Christina Schaub, Wolf Müller, Elena Sperk, Leonard Christopher Schmeel, Katharina Sahm, Christoph Oster, Sied Kebir, Peter Hambsch, Torsten Pietsch, Sotirios Bisdas, Michael Platten, Martin Glas, Clemens Seidel, Ulrich Herrlinger, Michael Hölzel.

The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.

DOI: https://doi.org/10.1038/s41467-024-48416-9
Proc Natl Acad Sci U S A. 2024 Jun 04. 121(23): e2318843121

Rapid detection of IDH mutations in gliomas by intraoperative mass spectrometry.

Wei Hua, Wenpeng Zhang, Hannah Brown, Junhan Wu, Xinqi Fang, Mahdiyeh Shahi, Rong Chen, Haoyue Zhang, Bin Jiao, Nan Wang, Hao Xu, Minjie Fu, Xiaowen Wang, Jinsen Zhang, Xin Zhang, Qijun Wang, Wei Zhu, Dan Ye, Diogo Moniz Garcia, Kaisorn Chaichana, R Graham Cooks, Zheng Ouyang, Ying Mao, Alfredo Quinones-Hinojosa.

  The development and performance of two mass spectrometry (MS) workflows for the intraoperative diagnosis of isocitrate dehydrogenase (IDH) mutations in glioma is implemented by independent teams at Mayo Clinic, Jacksonville, and Huashan Hospital, Shanghai. The infiltrative nature of gliomas makes rapid diagnosis necessary to guide the extent of surgical resection of central nervous system (CNS) tumors. The combination of tissue biopsy and MS analysis used here satisfies this requirement. The key feature of both described methods is the use of tandem MS to measure the oncometabolite 2-hydroxyglutarate (2HG) relative to endogenous glutamate (Glu) to characterize the presence of mutant tumor. The experiments i) provide IDH mutation status for individual patients and ii) demonstrate a strong correlation of 2HG signals with tumor infiltration. The measured ratio of 2HG to Glu correlates with IDH-mutant (IDH-mut) glioma (P < 0.0001) in the tumor core data of both teams. Despite using different ionization methods and different mass spectrometers, comparable performance in determining IDH mutations from core tumor biopsies was achieved with sensitivities, specificities, and accuracies all at 100%. None of the 31 patients at Mayo Clinic or the 74 patients at Huashan Hospital were misclassified when analyzing tumor core biopsies. Robustness of the methodology was evaluated by postoperative re-examination of samples. Both teams noted the presence of high concentrations of 2HG at surgical margins, supporting future use of intraoperative MS to monitor for clean surgical margins. The power of MS diagnostics is shown in resolving contradictory clinical features, e.g., in distinguishing gliosis from IDH-mut glioma.

Keywords:  2-hydroxyglutarate; intraoperative analysis; molecular diagnostics; oncometabolite; tandem mass spectrometry

DOI:  https://doi.org/10.1073/pnas.2318843121
Nat Commun. 2024 May 30. 15(1): 4616

Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy.

Faye M Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Sahiti Donthula, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana D Karam, Soudabeh Kargar, Natalie J Serkova, Nicholas K Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar, Nathan A Dahl.

Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.

DOI: https://doi.org/10.1038/s41467-024-48214-3
STAR Protoc. 2024 May 23. pii: S2666-1667(24)00244-2. [Epub ahead of print]5(2): 103079

Protocol to quantify immune cell distribution from the vasculature to the glioma microenvironment on sequential immunofluorescence multiplex images.

Hinda Najem, Sebastian Pacheco, Joanna Kowal, Dan Winkowski, Jared K Burks, Amy B Heimberger.

  Although myeloid-derived immune cells can be dispersed throughout the tumor microenvironment (TME), anti-tumor effector cells are confined to the perivascular space. Here, we present a protocol to quantify immune cell distribution from tumor vasculature to its glioma microenvironment on sequential immunofluorescence multiplex images. We describe steps for sequential immunofluorescence multiplex staining, image generation, and storage. We then detail the procedures for tissue, vessel, and nuclei segmentation; cell phenotyping; data extraction; and training using RStudio and Spyder.

Keywords:  Cancer; Immunology; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2024.103079
Nat Commun. 2024 May 27. 15(1): 4503

Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales.

Jochen Meyer, Kwanha Yu, Estefania Luna-Figueroa, Benjamin Deneen, Jeffrey Noebels.

The emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, expansion dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two glioblastoma mouse models with distinct synaptic microenvironments and infiltration profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is differentially modulated during periods of accelerated and inhibited tumor expansion. Abnormal glutamate accumulation precedes and outpaces the spatial extent of baseline neuronal calcium signaling, indicating these processes are uncoupled in tumor cortex. Distinctive excitability homeostasis patterns and functional connectivity of local and remote neuronal populations support the promise of precision genetic diagnosis and management of this devastating brain disease.

DOI: https://doi.org/10.1038/s41467-024-48757-5