bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–05–26
eight papers selected by
Oltea Sampetrean, Keio University
  1. Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.
  2. DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology.
  3. CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma.
  4. Unraveling the hypoxic puzzle: LncRNA LUCAT1 drives glioblastoma in cooperation with HIF1⍺.
  5. Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.
  6. Current immunotherapeutic approaches to diffuse intrinsic pontine glioma.
  7. BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma.
  8. Distinct roles of TREM2 in central nervous system cancers and peripheral cancers.
  1. bioRxiv. 2024 May 06. pii: 2024.05.03.592418. [Epub ahead of print]
    Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.
    Maria F Gonzalez-Aponte, Anna R Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Joshua B Rubin, Erik D Herzog.
      Glioblastoma (GBM) is the most common primary brain tumor in adults with a poor prognosis despite aggressive therapy. A recent, retrospective clinical study found that administering Temozolomide in the morning increased patient overall survival by 6 months compared to evening. Here, we tested the hypothesis that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We found daily Dexamethasone promoted or suppressed GBM growth depending on time of day of administration and on the clock gene, Bmal1 . Blocking circadian signals, like VIP or glucocorticoids, dramatically slowed GBM growth and disease progression. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression in vitro and in vivo that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, which modulates its growth through clock-controlled cues, like glucocorticoids.
    DOI:  https://doi.org/10.1101/2024.05.03.592418
  2. Neuro Oncol. 2024 Mar 22. pii: noae072. [Epub ahead of print]
    DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology.
    Rifaquat Rahman, Diana D Shi, Zachary J Reitman, Petra Hamerlik, John F de Groot, Daphne A Haas-Kogan, Alan D D'Andrea, Erik P Sulman, Kirk Tanner, Nathalie Y R Agar, Jann N Sarkaria, Christopher L Tinkle, Ranjit S Bindra, Minesh P Mehta, Patrick Y Wen.
      DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.
    Keywords:  DDR inhibitors; DNA damage response; DNA repair; glioma; radiation therapy
    DOI:  https://doi.org/10.1093/neuonc/noae072
  3. Cancer Discov. 2024 May 20.
    CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma.
    Xu Zhang, Shoufu Duan, Panagiota E Apostolou, Xiaoping Wu, Jun Watanabe, Matthew Gallitto, Tara Barron, Kathryn R Taylor, Pamelyn J Woo, Xu Hua, Hui Zhou, Hong-Jian Wei, Nicholas McQuillan, Kyung-Don Kang, Gregory K Friedman, Peter D Canoll, Kenneth Chang, Cheng-Chia Wu, Rintaro Hashizume, Christopher R Vakoc, Michelle Monje, Guy M McKhann, Joseph A Gogos, Zhiguo Zhang.
      High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0012
  4. Neuro Oncol. 2024 May 21. pii: noae096. [Epub ahead of print]
    Unraveling the hypoxic puzzle: LncRNA LUCAT1 drives glioblastoma in cooperation with HIF1⍺.
    Ying Zhang, Kadie Hudson, Roger Abounader.
      
    DOI:  https://doi.org/10.1093/neuonc/noae096
  5. Nat Commun. 2024 May 18. 15(1): 4241
    Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.
    Yulin Zhang, Kaiyan Xi, Zhipeng Fu, Yuying Zhang, Bo Cheng, Fan Feng, Yuanmin Dong, Zezheng Fang, Yi Zhang, Jianyu Shen, Mingrui Wang, Xu Han, Huimin Geng, Lei Sun, Xingang Li, Chen Chen, Xinyi Jiang, Shilei Ni.
      Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.
    DOI:  https://doi.org/10.1038/s41467-024-48606-5
  6. Front Genet. 2024 ;15 1349612
    Current immunotherapeutic approaches to diffuse intrinsic pontine glioma.
    Catherine Lin, Christian Smith, James Rutka.
      Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The median age at diagnosis is 6-7 years old, with less than 10% overall survival 2 years after diagnosis and less than 1% after 5 years. DIPGs are surgically inaccessible, and radiation therapy provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children, with a societal cancer burden in years of life lost (YLL) of more than 67 per individual, versus approximately 14 and 16 YLL for lung and breast cancer respectively. More than 95 clinical drug trials have been conducted on children with DIPGs, and all have failed to improve survival. No single or combination chemotherapeutic strategy has been successful to date because of our inability to identify targeted drugs for this disease and to deliver these drugs across an intact blood-brain barrier (BBB). Accordingly, there has been an increased focus on immunotherapy research in DIPG, with explorations into treatments such as chimeric antigen receptor T (CAR-T) cells, immune checkpoint blockades, cancer vaccines, and autologous cell transfer therapy. Here, we review the most recent advances in identifying genetic factors influencing the development of immunotherapy for DIPG. Additionally, we explore emerging technologies such as Magnetic Resonance-guided Focused Ultrasound (MRgFUS) in potential combinatorial approaches to treat DIPG.
    Keywords:  blood-brain barrier (BBB); brainstem; diffuse intrinsic pontine glioma (DIPG); glioma; immunotherapy
    DOI:  https://doi.org/10.3389/fgene.2024.1349612
  7. J Clin Invest. 2024 May 21. pii: e174794. [Epub ahead of print]
    BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma.
    Jun Watanabe, Matthew R Clutter, Michael J Gullette, Takahiro Sasaki, Eita Uchida, Savneet Kaur, Yan Mo, Kouki Abe, Yukitomo Ishi, Nozomu Takata, Manabu Natsumeda, Samantha Gadd, Zhiguo Zhang, Oren J Becher, Rintaro Hashizume.
      Diffuse midline glioma (DMG) H3K27-altered is one of the devastating childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation anti-tumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extra-terminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-seq and CUT & RUN showed that BET bromodomain inhibitors regulate the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation-response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.
    Keywords:  Brain cancer; Epigenetics; Oncology; Therapeutics; Translation
    DOI:  https://doi.org/10.1172/JCI174794
  8. Cancer Cell. 2024 May 17. pii: S1535-6108(24)00162-4. [Epub ahead of print]
    Distinct roles of TREM2 in central nervous system cancers and peripheral cancers.
    Jian Zhong, Xudong Xing, Yixin Gao, Lei Pei, Chenfei Lu, Huixin Sun, Yanxing Lai, Kang Du, Feizhe Xiao, Ying Yang, Xiuxing Wang, Yu Shi, Fan Bai, Nu Zhang.
      Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.
    Keywords:  TREM2; central nervous system cancer; glioblastoma; macrophage; microglia; myeloid cell; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2024.05.001
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