bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023‒11‒19
ten papers selected by
Oltea Sampetrean, Keio University
  1. Glioblastoma cells use an integrin- and CD44-mediated motor-clutch mode of migration in brain tissue.
  2. Neuronal activity promotes glioma progression by inducing proneural-to-mesenchymal transition in glioma stem cells.
  3. DeepAutoGlioma: a deep learning autoencoder-based multi-omics data integration and classification tools for glioma subtyping.
  4. Multi-omic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.
  5. Breaking the feed forward inflammatory cytokine loop in the tumor microenvironment of PDGFB-driven glioblastomas.
  6. Rewiring of cortical glucose metabolism fuels human brain cancer growth.
  7. Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas.
  8. Protocol for in vitro establishment of heterogeneous stem-like cultures derived from whole human glioblastoma tumors.
  9. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.
  10. Clinical impact of molecular profiling in rare brain tumors.
  1. bioRxiv. 2023 Oct 25. pii: 2023.10.23.563458. [Epub ahead of print]
    Glioblastoma cells use an integrin- and CD44-mediated motor-clutch mode of migration in brain tissue.
    Sarah M Anderson, Marcus Kelly, David J Odde.
      Glioblastoma (GBM) is an aggressive malignant brain tumor with 2-year survival rates of 6.7% [1], [2]. One key characteristic of the disease is the ability of glioblastoma cells to migrate rapidly and spread throughout healthy brain tissue[3], [4]. To develop treatments that effectively target cell migration, it is important to understand the fundamental mechanism driving cell migration in brain tissue. Here we utilized confocal imaging to measure traction dynamics and migration speeds of glioblastoma cells in mouse organotypic brain slices to identify the mode of cell migration. Through imaging cell-vasculature interactions and utilizing drugs, antibodies, and genetic modifications to target motors and clutches, we find that glioblastoma cell migration is most consistent with a motor-clutch mechanism to migrate through brain tissue ex vivo , and that both integrins and CD44, as well as myosin motors, play an important role in constituting the adhesive clutch.
    DOI:  https://doi.org/10.1101/2023.10.23.563458
  2. Cancer Res. 2023 Nov 14.
    Neuronal activity promotes glioma progression by inducing proneural-to-mesenchymal transition in glioma stem cells.
    Xiaofan Guo, Wei Qiu, Chaochao Wang, Yanhua Qi, Boyan Li, Shaobo Wang, Rongrong Zhao, Bo Cheng, Xiao Han, Hao Du, Zijie Gao, Ziwen Pan, Shulin Zhao, Gang Li, Hao Xue.
      Neuronal activity can drive progression of high-grade glioma by mediating mitogen production and neuron-glioma synaptic communications. Glioma stem cells (GSCs) also play a significant role in progression, therapy resistance, and recurrence in glioma, which implicates potential crosstalk between neuronal activity and GSC biology. Here, we manipulated neuronal activity using chemogenetics in vitro and in vivo to study how it influences GSCs. Neuronal activity supported glioblastoma progression and radioresistance through exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. Molecularly, neuronal activation led to elevated miR-184-3p in neuron-derived exosomes that were taken up by GSCs and reduced the mRNA N6-methyladenosine (m6A) levels by inhibiting RBM15 expression. RBM15 deficiency decreased m6A modification of DLG3 mRNA and subsequently induced GSC PMT by activating the STAT3 pathway. Loss of miR-184-3p in cortical neurons reduced GSC xenograft growth, even when neurons were activated. Levetiracetam, an antiepileptic drug, reduced the neuronal production of miR-184-3p-enriched exosomes, inhibited GSC PMT, and increased radiosensitivity of tumors to prolong survival in xenograft mouse models. Together, these findings indicate that exosomes derived from active neurons promote glioblastoma progression and radioresistance by inducing PMT of GSCs.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0609
  3. BioData Min. 2023 Nov 15. 16(1): 32
    DeepAutoGlioma: a deep learning autoencoder-based multi-omics data integration and classification tools for glioma subtyping.
    Sana Munquad, Asim Bikas Das.
      BACKGROUND AND OBJECTIVE: The classification of glioma subtypes is essential for precision therapy. Due to the heterogeneity of gliomas, the subtype-specific molecular pattern can be captured by integrating and analyzing high-throughput omics data from different genomic layers. The development of a deep-learning framework enables the integration of multi-omics data to classify the glioma subtypes to support the clinical diagnosis.RESULTS: Transcriptome and methylome data of glioma patients were preprocessed, and differentially expressed features from both datasets were identified. Subsequently, a Cox regression analysis determined genes and CpGs associated with survival. Gene set enrichment analysis was carried out to examine the biological significance of the features. Further, we identified CpG and gene pairs by mapping them in the promoter region of corresponding genes. The methylation and gene expression levels of these CpGs and genes were embedded in a lower-dimensional space with an autoencoder. Next, ANN and CNN were used to classify subtypes using the latent features from embedding space. CNN performs better than ANN for subtyping lower-grade gliomas (LGG) and glioblastoma multiforme (GBM). The subtyping accuracy of CNN was 98.03% (± 0.06) and 94.07% (± 0.01) in LGG and GBM, respectively. The precision of the models was 97.67% in LGG and 90.40% in GBM. The model sensitivity was 96.96% in LGG and 91.18% in GBM. Additionally, we observed the superior performance of CNN with external datasets. The genes and CpGs pairs used to develop the model showed better performance than the random CpGs-gene pairs, preprocessed data, and single omics data.
    CONCLUSIONS: The current study showed that a novel feature selection and data integration strategy led to the development of DeepAutoGlioma, an effective framework for diagnosing glioma subtypes.
    Keywords:  Autoencoder; Convolutional neural network (CNN); Glioblastoma multiforme (GBM); Lower-grade glioma (LGG); Multi-omics
    DOI:  https://doi.org/10.1186/s13040-023-00349-7
  4. J Clin Invest. 2023 Nov 16. pii: e170397. [Epub ahead of print]
    Multi-omic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.
    Joseph H Garcia, Erin A Akins, Saket Jain, Kayla J Wolf, Jason Zhang, Nikita Choudhary, Meeki Lad, Poojan Shukla, Jennifer Rios, Kyounghee Seo, Sabraj A Gill, William H Carson, Luis R Carrete, Allison C Zheng, David R Raleigh, Sanjay Kumar, Manish K Aghi.
      While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma-lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.
    Keywords:  Amino acid metabolism; Bioenergetics; Brain cancer; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI170397
  5. J Clin Invest. 2023 Nov 15. pii: e175127. [Epub ahead of print]133(22):
    Breaking the feed forward inflammatory cytokine loop in the tumor microenvironment of PDGFB-driven glioblastomas.
    C Ryan Miller, Anita B Hjelmeland.
      Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1β in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow-derived myeloid cells (BMDMs). In contrast, no requirement for IL-1β was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti-IL-1β or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.
    DOI:  https://doi.org/10.1172/JCI175127
  6. medRxiv. 2023 Oct 25. pii: 2023.10.24.23297489. [Epub ahead of print]
    Rewiring of cortical glucose metabolism fuels human brain cancer growth.
    Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Sravya Palavalasa, Abhinav Achreja, Alexandra O'Brien, Ayesha U Kothari, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Donna M Edwards, Zhe Wu, Jiane Feng, Anthony C Andren, Li Zhang, Vijay Tarnal, Kimberly A Redic, Nathan Qi, Joshua Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.
      The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13 C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth.Significance: This study is the first to directly measure biosynthetic flux in both glioma and cortical tissue in human brain cancer patients. Brain tumors rewire glucose carbon utilization away from oxidation and neurotransmitter production towards biosynthesis to fuel growth. Blocking these metabolic adaptations with dietary interventions slows brain cancer growth with minimal effects on cortical metabolism.
    DOI:  https://doi.org/10.1101/2023.10.24.23297489
  7. bioRxiv. 2023 Oct 27. pii: 2023.10.24.563466. [Epub ahead of print]
    Programs, Origins, and Niches of Immunomodulatory Myeloid Cells in Gliomas.
    Tyler E Miller, Chadi A El Farran, Charles P Couturier, Zeyu Chen, Joshua P D'Antonio, Julia Verga, Martin A Villanueva, L Nicolas Gonzalez Castro, Yuzhou Evelyn Tong, Tariq Al Saadi, Andrew N Chiocca, David S Fischer, Dieter Henrik Heiland, Jennifer L Guerriero, Kevin Petrecca, Mario L Suva, Alex K Shalek, Bradley E Bernstein.
      Gliomas are incurable malignancies notable for an immunosuppressive microenvironment with abundant myeloid cells whose immunomodulatory properties remain poorly defined. Here, utilizing scRNA-seq data for 183,062 myeloid cells from 85 human tumors, we discover that nearly all glioma-associated myeloid cells express at least one of four immunomodulatory activity programs: Scavenger Immunosuppressive, C1Q Immunosuppressive, CXCR4 Inflammatory, and IL1B Inflammatory. All four programs are present in IDH1 mutant and wild-type gliomas and are expressed in macrophages, monocytes, and microglia whether of blood or resident myeloid cell origins. Integrating our scRNA-seq data with mitochondrial DNA-based lineage tracing, spatial transcriptomics, and organoid explant systems that model peripheral monocyte infiltration, we show that these programs are driven by microenvironmental cues and therapies rather than myeloid cell type, origin, or mutation status. The C1Q Immunosuppressive program is driven by routinely administered dexamethasone. The Scavenger Immunosuppressive program includes ligands with established roles in T-cell suppression, is induced in hypoxic regions, and is associated with immunotherapy resistance. Both immunosuppressive programs are less prevalent in lower-grade gliomas, which are instead enriched for the CXCR4 Inflammatory program. Our study provides a framework to understand immunomodulatory myeloid cells in glioma, and a foundation to develop more effective immunotherapies.
    DOI:  https://doi.org/10.1101/2023.10.24.563466
  8. STAR Protoc. 2023 Nov 14. pii: S2666-1667(23)00672-X. [Epub ahead of print]4(4): 102705
    Protocol for in vitro establishment of heterogeneous stem-like cultures derived from whole human glioblastoma tumors.
    Francesca De Bacco, Francesca Orzan, Elena Casanova, Marta Prelli, Carla Boccaccio.
      Cultures enriched in glioblastoma stem-like cells (GSCs) are prominent in vitro models to investigate molecular determinants and therapeutic targets of glioblastoma; however, conventional GSC derivation protocols fail to preserve GSC heterogeneity. Here, we present a protocol for the propagation of heterogeneous GSC cultures starting from cell resuspensions containing the entire tumor mass. We describe steps for isolation of GSCs and their maintenance and expansion in culture. We then detail procedures for preliminary analysis to be performed on freshly isolated material. For complete details on the use and execution of this protocol, please refer to De Bacco et al.1.
    Keywords:  Cancer; Cell culture; Cell isolation; Flow Cytometry; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2023.102705
  9. Nat Med. 2023 Nov 17.
    The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.
    Lindsay B Kilburn, Dong-Anh Khuong-Quang, Jordan R Hansford, Daniel Landi, Jasper van der Lugt, Sarah E S Leary, Pablo Hernáiz Driever, Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Angela J Waanders, David S Ziegler, Olaf Witt, Patricia A Baxter, Hyoung Jin Kang, Timothy E Hassall, Jung Woo Han, Darren Hargrave, Andrea T Franson, Michal Yalon Oren, Helen Toledano, Valérie Larouche, Cassie Kline, Mohamed S Abdelbaki, Nada Jabado, Nicholas G Gottardo, Nicolas U Gerber, Nicholas S Whipple, Devorah Segal, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine Mueller, Izzy Cornelio, Lisa McLeod, Xin Zhao, Ashley Walter, Daniel Da Costa, Peter Manley, Samuel C Blackman, Roger J Packer, Karsten Nysom.
      BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .
    DOI:  https://doi.org/10.1038/s41591-023-02668-y
  10. Curr Opin Neurol. 2023 Dec 01. 36(6): 579-586
    Clinical impact of molecular profiling in rare brain tumors.
    Drew Pratt, Marta Penas-Prado, Mark R Gilbert.
      PURPOSE OF REVIEW: The purpose of this review is to describe the commonly used molecular diagnostics and illustrate the prognostic importance to the more accurate diagnosis that also may uncover therapeutic targets.RECENT FINDINGS: The most recent WHO Classification of Central Nervous System Tumours (2021) lists over 100 distinct tumor types. While traditional histology continues to be an important component, molecular testing is increasingly being incorporated as requisite diagnostic criteria. Specific molecular findings such as co-deletion of the short arm of chromosome 1 (1p) and long arm of chromosome 19 (19q) now define IDH-mutant gliomas as oligodendroglioma. In recent years, DNA methylation profiling has emerged as a dynamic tool with high diagnostic accuracy. The integration of specific genetic (mutations, fusions) and epigenetic (CpG methylation) alterations has led to diagnostic refinement and the discovery of rare brain tumor types with distinct clinical outcomes. Molecular profiling is anticipated to play an increasing role in routine surgical neuropathology, although costs, access, and logistical concerns remain challenging.
    SUMMARY: This review summarizes the current state of molecular testing in neuro-oncology highlighting commonly used and developing technologies, while also providing examples of new tumor types/subtypes that have emerged as a result of improved diagnostic precision.
    DOI:  https://doi.org/10.1097/WCO.0000000000001211
This page is being maintained by Thomas Krichel. It was last updated on 2023‒11‒26 at 0:14.