bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–09–01
nine papers selected by
Oltea Sampetrean, Keio University
  1. Lipid transfer from tumour-associated macrophages supports glioblastoma.
  2. Next-generation CAR T cell therapies for glioblastoma.
  3. Microbiota and glioma: a new perspective from association to clinical translation.
  4. Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities.
  5. Single-cell dissection of the human blood-brain barrier and glioma blood-tumor barrier.
  6. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
  7. The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis.
  8. Glioblastoma-derived exosomes promote lipid accumulation and induce ferroptosis in dendritic cells via the NRF2/GPX4 pathway.
  9. TLR agonists promote formation of Tertiary Lymphoid Structure and improve anti-glioma immunity.
  1. Nat Rev Immunol. 2024 Aug 23.
    Lipid transfer from tumour-associated macrophages supports glioblastoma.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01086-6
  2. Sci Transl Med. 2024 Aug 28. 16(762): eadp2660
    Next-generation CAR T cell therapies for glioblastoma.
    Joshua D Bernstock, Jakob V E Gerstl, Pablo A Valdés, Gregory K Friedman, E Chiocca.
      Interim results from two phase 1 trials demonstrate progress in the use of chimeric antigen receptor (CAR) T cell therapy for recurrent glioblastoma (GBM).
    DOI:  https://doi.org/10.1126/scitranslmed.adp2660
  3. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2394166
    Microbiota and glioma: a new perspective from association to clinical translation.
    Wenhui Wang, Zihao Ou, Xixin Huang, Jingyu Wang, Qianbei Li, Minghui Wen, Lei Zheng.
      Gliomas pose a significant challenge in oncology due to their malignant nature, aggressive growth, frequent recurrence, and complications posed by the blood-brain barrier. Emerging research has revealed the critical role of gut microbiota in influencing health and disease, indicating its possible impact on glioma pathogenesis and treatment responsiveness. This review focused on existing evidence and hypotheses on the relationship between microbiota and glioma from progression to invasion. By discussing possible mechanisms through which microbiota may affect glioma biology, this paper offers new avenues for targeted therapies and precision medicine in oncology.
    Keywords:  Microbiota; glioma; mechanism; noninvasive diagnostics; targeted therapy
    DOI:  https://doi.org/10.1080/19490976.2024.2394166
  4. Cancer Res. 2024 Aug 26.
    Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities.
    Graham MacLeod, Fatemeh Molaei, Shahan Haider, Maira P Almeida, Sichun Lin, Michelle Kushida, Haresh Sureshkumar, Jasmine K Bhatti, Jack Q Lu, Daniel Schramek, Peter B Dirks, Stephane Angers.
      Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults and is driven by self-renewing glioblastoma stem cells (GSCs) that persist after therapy and seed treatment refractory recurrent tumors. GBM tumors display a high degree of intra- and inter-tumoral heterogeneity that is a prominent barrier to targeted treatment strategies. This heterogeneity extends to GSCs that exist on a gradient between two transcriptional states or subtypes termed developmental and injury-response. Drug targets for each subtype are needed to effectively target GBM. To identify conserved and subtype-specific genetic dependencies across a large and heterogeneous panel of GSCs, we designed the GBM5K targeted gRNA library and performed fitness screens in a total of 30 patient-derived GSC cultures. The focused CRISPR screens identified the most conserved subtype-specific vulnerabilities in GSCs and elucidated the functional dependency gradient existing between the developmental and injury-response states. Developmental-specific fitness genes were enriched for transcriptional regulators of neurodevelopment, whereas injury-response-specific fitness genes were highlighted by several genes implicated in integrin and focal adhesion signaling. These context-specific vulnerabilities conferred differential sensitivity to inhibitors of β1 integrin, FAK, MEK and OLIG2. Interestingly, the screens revealed that the subtype-specific signaling pathways drive differential cyclin D (CCND1 vs. CCND2) dependencies between subtypes. These data provide biological insight and mechanistic understanding of GBM heterogeneity and point to opportunities for precision targeting of defined GBM and GSC subtypes to tackle heterogeneity.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-4024
  5. Neuron. 2024 Aug 19. pii: S0896-6273(24)00571-3. [Epub ahead of print]
    Single-cell dissection of the human blood-brain barrier and glioma blood-tumor barrier.
    Yuan Xie, Fan Yang, Liqun He, Hua Huang, Min Chao, Haiyan Cao, Yaqin Hu, Zhicheng Fan, Yaohong Zhai, Wenjian Zhao, Xian Liu, Ruozhu Zhao, Bing Xiao, Xinxin Shi, Yuancheng Luo, Jinlong Yin, Dayun Feng, Jean-Philippe Hugnot, Lars Muhl, Anna Dimberg, Christer Betsholtz, Yanyu Zhang, Liang Wang, Lei Zhang.
      The blood-brain barrier (BBB) serves as a crucial vascular specialization, shielding and nourishing brain neurons and glia while impeding drug delivery. Here, we conducted single-cell mRNA sequencing of human cerebrovascular cells from 13 surgically resected glioma samples and adjacent normal brain tissue. The transcriptomes of 103,230 cells were mapped, including 57,324 endothelial cells (ECs) and 27,703 mural cells (MCs). Both EC and MC transcriptomes originating from lower-grade glioma were indistinguishable from those of normal brain tissue, whereas transcriptomes from glioblastoma (GBM) displayed a range of abnormalities. Among these, we identified LOXL2-dependent collagen modification as a common GBM-dependent trait and demonstrated that inhibiting LOXL2 enhanced chemotherapy efficacy in both murine and human patient-derived xenograft (PDX) GBM models. Our comprehensive single-cell RNA sequencing-based molecular atlas of the human BBB, coupled with insights into its perturbations in GBM, holds promise for guiding future investigations into brain health, pathology, and therapeutic strategies.
    Keywords:  BBB; BTB; blood-tumor barrier; collagen; drug delivery; endothelial cells; human blood-brain barrier; pericytes; scRNA-seq; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.neuron.2024.07.026
  6. EMBO J. 2024 Aug 27.
    A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
    Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll.
      Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.
    Keywords:  Astrocytic; Ferroptosis; Glioma; Mitochondrial-metabolism; Quiescent
    DOI:  https://doi.org/10.1038/s44318-024-00176-4
  7. Nat Commun. 2024 Aug 28. 15(1): 7455
    The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis.
    Wentao Zhao, Cong Ouyang, Liang Zhang, Jinyang Wang, Jiaojiao Zhang, Yan Zhang, Chen Huang, Qiao Xiao, Bin Jiang, Furong Lin, Cixiong Zhang, Mingxia Zhu, Changchuan Xie, Xi Huang, Bingchang Zhang, Wenpeng Zhao, Jiawei He, Sifang Chen, Xiyao Liu, Donghai Lin, Qinxi Li, Zhanxiang Wang.
      Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.
    DOI:  https://doi.org/10.1038/s41467-024-51444-0
  8. Front Immunol. 2024 ;15 1439191
    Glioblastoma-derived exosomes promote lipid accumulation and induce ferroptosis in dendritic cells via the NRF2/GPX4 pathway.
    Jian Yang, Mingqi Zhang, Xuying Zhang, Yue Zhou, Tingting Ma, Jia Liang, Jinyi Zhang.
      Glioblastoma-derived exosomes (GDEs), containing nucleic acids, proteins, fatty acids and other substances, perform multiple important functions in glioblastoma microenvironment. Tumor-derived exosomes serve as carriers of fatty acids and induce a shift in metabolism towards oxidative phosphorylation, thus driving immune dysfunction of dendritic cells (DCs). Lipid peroxidation is an important characteristic of ferroptosis. Nevertheless, it remains unclear whether GDEs can induce lipid accumulation and lipid oxidation to trigger ferroptosis in DCs. In our study, we investigate the impact of GDEs on lipid accumulation and oxidation in DCs by inhibiting GDEs secretion through knocking down the expression of Rab27a using a rat orthotopic glioblastoma model. The results show that inhibiting the secretion of GDEs can reduce lipid accumulation in infiltrating DCs in the brain and decrease mature dendritic cells (mDCs) lipid peroxidation levels, thereby suppressing glioblastoma growth. Mechanistically, we employed in vitro treatments of bone marrow-derived dendritic cells (BMDCs) with GDEs. The results indicate that GDEs decrease the viability of mDCs compared to immature dendritic cells (imDCs) and trigger ferroptosis in mDCs via the NRF2/GPX4 pathway. Overall, these findings provide new insights into the development of immune-suppressive glioblastoma microenvironment through the interaction of GDEs with DCs.
    Keywords:  dendritic cells; exosomes; ferroptosis; glioblastoma; lipid accumulation
    DOI:  https://doi.org/10.3389/fimmu.2024.1439191
  9. Neuro Oncol. 2024 Aug 27. pii: noae167. [Epub ahead of print]
    TLR agonists promote formation of Tertiary Lymphoid Structure and improve anti-glioma immunity.
    Shaoping Shen, Yong Cui, Mingxiao Li, Kefu Yu, Qinghui Zhu, Xiaokang Zhang, Weicheng Shen, Haoyi Li, Haihui Jiang, Ming Li, Xijie Wang, Xuzhe Zhao, Xiaohui Ren, Song Lin.
       BACKGROUND: Glioma, characterized by limited lymphocytic infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study aims to explore therapeutic strategies for inducing tertiary lymphoid structure (TLS) formation within the glioma microenvironment (GME) to transition it from an immune-resistant to an activated state.
    METHODS: TLS formation in GME was successfully induced by intracranial administration of Toll-like receptor (TLR) agonists (OK-432, TLR2/4/9 agonist) and glioma antigens (i.c. αTLR-mix). We employed staining analysis, antibody neutralization, single-cell RNA sequencing (scRNA-Seq), and BCR/TCR sequencing to investigate the underlying mechanisms of TLS formation and its role in anti-glioma immunity. Additionally, a preliminary translational clinical study was conducted.
    RESULTS: TLS formation correlated with increased lymphocyte infiltration in GME and led to improved prognosis in glioma-bearing mice. In the study of TLS induction mechanisms, certain macrophages/microglia and Th17 displayed markers of "LTo" and "LTi" cells, respectively, interaction through LTα/β-LTβR promoted TLS induction. Post-TLS formation, CD4+ and CD8+ T cells but not CD19+ B cells contributed to anti-glioma immunity. Comparative analysis of B/T cells between brain and lymph node showed that brain B/T cells unveiled switch from naïve to mature, some B cells highlighted an enrichment of CSR-associated genes, V gene usage and clonotype bias were observed. In related clinical studies, i.c. αTLR-mix treatment exhibited tolerability, and chemokines/cytokines assay provided preliminary evidence supporting TLS formation in GME.
    CONCLUSION: TLS induction in GME enhanced anti-glioma immunity, improved the immune microenvironment, and controlled glioma growth, suggesting potential therapeutic avenues for treating glioma in the future.
    Keywords:   in situ treatment; Glioma immunotherapy; TLR agonists; Tertiary Lymphoid Structure
    DOI:  https://doi.org/10.1093/neuonc/noae167
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