bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–09–17
ten papers selected by
Oltea Sampetrean, Keio University
  1. Combined inhibition of topoisomerase I and poly(ADP-ribose) polymerase: A synergistic therapeutic strategy for glioblastoma with phosphatase and tensin homolog deficiency.
  2. Translocator protein (18kDA) (TSPO) marks mesenchymal glioblastoma cell populations characterized by elevated numbers of tumor-associated macrophages.
  3. Gene therapy using genome-edited iPS cells for targeting malignant glioma.
  4. A designer peptide against the EAG2-Kvβ2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma.
  5. Dissecting the tumor microenvironment of epigenetically driven gliomas: Opportunities for single-cell and spatial multiomics.
  6. Let the Guard Down: cAMP Activators Can Improve Immunotherapy in GBM.
  7. Diffuse Midline Glioma Invasion and Metastasis Rely on Cell-autonomous Signaling.
  8. The INDIGO Trial: Precision Medicine Finally Comes to Glioma.
  9. Glioma genetic profiles associated with electrophysiologic hyperexcitability.
  10. Microdevice Provides Drug Response Readouts In Situ.
  1. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad102
    Combined inhibition of topoisomerase I and poly(ADP-ribose) polymerase: A synergistic therapeutic strategy for glioblastoma with phosphatase and tensin homolog deficiency.
    Olga Kim, Madison Butler, Zach Sergi, Robert W Robey, Meili Zhang, Raj Chari, Ying Pang, Guangyang Yu, Wei Zhang, Hua Song, Dionne Davis, Robert G Hawley, Xinyu Wen, Herui Wang, Martha Quezado, Bao Tran, Mythili Merchant, Alice Ranjan, Frank B Furnari, Javed Khan, Mark R Gilbert, Christopher Ryan Miller, Michael M Gottesman, Yves Pommier, Jing Wu.
       Background: Deletions or loss-of-function mutations in phosphatase and tensin homolog (PTEN) are common in glioblastoma (GBM) and have been associated with defective DNA damage repair. Here we investigated whether PTEN deficiency presents a vulnerability to a simultaneous induction of DNA damage and suppression of repair mechanisms by combining topoisomerase I (TOP1) and PARP inhibitors.
    Methods: Patient-derived GBM cells and isogenic PTEN-null and PTEN-WT glioma cells were treated with LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor alone and in combination with a PARP inhibitor, Olaparib or Niraparib. RNAseq analysis was performed to identify treatment-induced dysregulated pathways.
    Results: We found that GBM cells lacking PTEN expression are highly sensitive to LMP400; however, rescue of the PTEN expression reduces sensitivity to the treatment. Combining LMP400 with Niraparib leads to synergistic cytotoxicity by inducing G2/M arrest, DNA damage, suppression of homologous recombination-related proteins, and activation of caspase 3/7 activity significantly more in PTEN-null cells compared to PTEN-WT cells. LMP400 and Niraparib are not affected by ABCB1 and ABCG2, the major ATP-Binding Cassette (ABC) drug efflux transporters expressed at the blood-brain barrier (BBB), thus suggesting BBB penetration which is a prerequisite for potential brain tumor treatment. Animal studies confirmed both an anti-glioma effect and sufficient BBB penetration to prolong survival of mice treated with the drug combination.
    Conclusions: Our findings provide a proof of concept for the combined treatment with LMP400 and Niraparib in a subset of GBM patients with PTEN deficiency.
    DOI:  https://doi.org/10.1093/noajnl/vdad102
  2. Acta Neuropathol Commun. 2023 Sep 11. 11(1): 147
    Translocator protein (18kDA) (TSPO) marks mesenchymal glioblastoma cell populations characterized by elevated numbers of tumor-associated macrophages.
    Lorraine Weidner, Julia Lorenz, Stefanie Quach, Frank K Braun, Tanja Rothhammer-Hampl, Laura-Marie Ammer, Arabel Vollmann-Zwerenz, Laura M Bartos, Franziska J Dekorsy, Adrien Holzgreve, Sabrina V Kirchleitner, Niklas Thon, Tobias Greve, Viktoria Ruf, Jochen Herms, Stefanie Bader, Vladimir M Milenkovic, Louisa von Baumgarten, Ayse N Menevse, Abir Hussein, Julian Sax, Christian H Wetzel, Rainer Rupprecht, Martin Proescholdt, Nils O Schmidt, Philipp Beckhove, Peter Hau, Joerg-Christian Tonn, Peter Bartenstein, Matthias Brendel, Nathalie L Albert, Markus J Riemenschneider.
      TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing.We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages.In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions.
    Keywords:  Glioma; Imaging; Immunohistochemistry; Intratumoral heterogeneity; Microglia; Myeloid cells; PET; Promotor methylation; RNA seq; TSPO
    DOI:  https://doi.org/10.1186/s40478-023-01651-5
  3. Bioeng Transl Med. 2023 Sep;8(5): e10406
    Gene therapy using genome-edited iPS cells for targeting malignant glioma.
    Ryota Tamura, Hiroyuki Miyoshi, Kent Imaizumi, Masahiro Yo, Yoshitaka Kase, Tsukika Sato, Mizuto Sato, Yukina Morimoto, Oltea Sampetrean, Jun Kohyama, Munehisa Shinozaki, Atsushi Miyawaki, Kazunari Yoshida, Hideyuki Saya, Hideyuki Okano, Masahiro Toda.
      Glioblastoma is characterized by diffuse infiltration into the normal brain. Invasive glioma stem cells (GSCs) are an underlying cause of treatment failure. Despite the use of multimodal therapies, the prognosis remains dismal. New therapeutic approach targeting invasive GSCs is required. Here, we show that neural stem cells (NSCs) derived from CRISRP/Cas9-edited human-induced pluripotent stem cell (hiPSC) expressing a suicide gene had higher tumor-trophic migratory capacity compared with mesenchymal stem cells (MSCs), leading to marked in vivo antitumor effects. High migratory capacity in iPSC-NSCs was related to self-repulsive action and pathotropism involved in EphB-ephrinB and CXCL12-CXCR4 signaling. The gene insertion to ACTB provided higher and stable transgene expression than other common insertion sites, such as GAPDH or AAVS1. Ferroptosis was associated with enhanced antitumor immune responses. The thymidylate synthase and dihydroprimidine dehydrogenase expressions predicted the treatment efficacy of therapeutic hiPSC-NSCs. Our results indicate the potential benefit of genome-edited iPS cells based gene therapy for invasive GSCs. Furthermore, the present research concept may become a platform to promote clinical studies using hiPSC.
    Keywords:  CRISPR/Cas9; ferroptosis; gene therapy; glioblastoma; migration
    DOI:  https://doi.org/10.1002/btm2.10406
  4. Nat Cancer. 2023 Sep 11.
    A designer peptide against the EAG2-Kvβ2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma.
    Weifan Dong, Adam Fekete, Xiaodi Chen, Hongwei Liu, Greg L Beilhartz, Xin Chen, Shahrzad Bahrampour, Yi Xiong, Qi Yang, Hongyu Zhao, Tian Kong, Malia S Morioka, Geena Jung, Ji-Eun Kim, Daniel Schramek, Peter B Dirks, Yuanquan Song, Tae-Hee Kim, Ye He, Siyi Wanggou, Xuejun Li, Roman A Melnyk, Lu-Yang Wang, Xi Huang.
      Glioblastoma (GBM) is an incurable brain cancer that lacks effective therapies. Here we show that EAG2 and Kvβ2, which are predominantly expressed by GBM cells at the tumor-brain interface, physically interact to form a potassium channel complex due to a GBM-enriched Kvβ2 isoform. In GBM cells, EAG2 localizes at neuron-contacting regions in a Kvβ2-dependent manner. Genetic knockdown of the EAG2-Kvβ2 complex decreases calcium transients of GBM cells, suppresses tumor growth and invasion and extends the survival of tumor-bearing mice. We engineered a designer peptide to disrupt EAG2-Kvβ2 interaction, thereby mitigating tumor growth in patient-derived xenograft and syngeneic mouse models across GBM subtypes without overt toxicity. Neurons upregulate chemoresistant genes in GBM cells in an EAG2-Kvβ2-dependent manner. The designer peptide targets neuron-associated GBM cells and possesses robust efficacy in treating temozolomide-resistant GBM. Our findings may lead to the next-generation therapeutic agent to benefit patients with GBM.
    DOI:  https://doi.org/10.1038/s43018-023-00626-8
  5. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad101
    Dissecting the tumor microenvironment of epigenetically driven gliomas: Opportunities for single-cell and spatial multiomics.
    Jonathan H Sussman, Jason Xu, Nduka Amankulor, Kai Tan.
      Malignant gliomas are incurable brain neoplasms with dismal prognoses and near-universal fatality, with minimal therapeutic progress despite billions of dollars invested in research and clinical trials over the last 2 decades. Many glioma studies have utilized disparate histologic and genomic platforms to characterize the stunning genomic, transcriptomic, and immunologic heterogeneity found in gliomas. Single-cell and spatial omics technologies enable unprecedented characterization of heterogeneity in solid malignancies and provide a granular annotation of transcriptional, epigenetic, and microenvironmental states with limited resected tissue. Heterogeneity in gliomas may be defined, at the broadest levels, by tumors ostensibly driven by epigenetic alterations (IDH- and histone-mutant) versus non-epigenetic tumors (IDH-wild type). Epigenetically driven tumors are defined by remarkable transcriptional programs, immunologically distinct microenvironments, and incompletely understood topography (unique cellular neighborhoods and cell-cell interactions). Thus, these tumors are the ideal substrate for single-cell multiomic technologies to disentangle the complex intra-tumoral features, including differentiation trajectories, tumor-immune cell interactions, and chromatin dysregulation. The current review summarizes the applications of single-cell multiomics to existing datasets of epigenetically driven glioma. More importantly, we discuss future capabilities and applications of novel multiomic strategies to answer outstanding questions, enable the development of potent therapeutic strategies, and improve personalized diagnostics and treatment via digital pathology.
    Keywords:  IDH-mutant glioma; Single-cell sequencing; Spatial omics; histone-mutant glioma; pediatric glioma
    DOI:  https://doi.org/10.1093/noajnl/vdad101
  6. Cancer Immunol Res. 2023 Sep 12. OF1-OF2
    Let the Guard Down: cAMP Activators Can Improve Immunotherapy in GBM.
    Juyeun Lee, Kristen E Kay, Michael A Vogelbaum, Justin D Lathia.
      Enhancing T-cell infiltration into glioblastoma (GBM) tumors has proven challenging yet remains crucial for improving the efficacy of immunotherapy for patients with this deadly cancer. In this issue, Qin, Huang, Li, and colleagues find that inhibiting vasculature formation driven by cancer stem cells is a promising target to enhance immunotherapy in GBM. See related article by Qin et al. (2).
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0667
  7. Neuro Oncol. 2023 Sep 13. pii: noad161. [Epub ahead of print]
    Diffuse Midline Glioma Invasion and Metastasis Rely on Cell-autonomous Signaling.
    Marco Bruschi, Lilia Midjek, Yassine Ajlil, Stephanie Vairy, Manon Lancien, Samia Ghermaoui, Thomas Kergrohen, Maïté Verreault, Ahmed Idbaih, Carlos Alberto Oliveira de Biagi, Ilon Liu, Mariella G Filbin, Kévin Beccaria, Thomas Blauwblomme, Stephanie Puget, Arnault Tauziede-Espariat, Pascale Varlet, Volodia Dangouloff-Ros, Nathalie Boddaert, Gwenael Le Teuff, Jacques Grill, Guillaume Montagnac, Nadia Elkhatib, Marie-Anne Debily, David Castel.
       BACKGROUND: Diffuse midline gliomas (DMG) are pediatric tumors with negligible two-year survival after diagnosis characterized by their ability to infiltrate the central nervous system. In the hope of controlling the local growth and slowing the disease all patients receive radiotherapy. However, distant progression occurs frequently in DMG patients. Current clues as to what causes tumor infiltration circle mainly around the tumor microenvironment, but there are currently no known determinants to predict the degree of invasiveness.
    METHODS: In this study we use patient-derived glioma stem cells (GSCs) to create patient-specific 3D avatars to model interindividual invasion and elucidate the cellular supporting mechanisms.
    RESULTS: We show that GSC models in 3D mirror the invasive behavior of the parental tumors, thus proving the ability of DMG to infiltrate as an autonomous characteristic of tumor cells. Furthermore, we distinguished two modes of migration, mesenchymal and amoeboid-like, and associated the amoeboid-like modality with GSCs derived from the most invasive tumors. Using transcriptomics of both organoids and primary tumors, we further characterized the invasive amoeboid-like tumors as oligodendrocyte progenitor-like, with highly contractile cytoskeleton and reduced adhesion ability driven by crucial over-expression of BMP7. Finally, we deciphered MEK, ERK and Rho/ROCK kinases activated downstream of the BMP7 stimulation as actionable targets controlling tumor cell motility.
    CONCLUSIONS: Our findings identify two new therapeutic avenues. First, patient-derived GSCs represent a predictive tool for patient stratification in order to adapt irradiation strategies. Second, autocrine and short-range BMP7-related signaling becomes a druggable target to prevent DMG spread and metastasis.
    Keywords:  DMG-H3K27M; GSC; Invasion; Metastasis; Tumor organoids
    DOI:  https://doi.org/10.1093/neuonc/noad161
  8. Neuro Oncol. 2023 Sep 12. pii: noad162. [Epub ahead of print]
    The INDIGO Trial: Precision Medicine Finally Comes to Glioma.
    Diana D Shi, William G Kaelin.
      
    DOI:  https://doi.org/10.1093/neuonc/noad162
  9. Neuro Oncol. 2023 Sep 15. pii: noad176. [Epub ahead of print]
    Glioma genetic profiles associated with electrophysiologic hyperexcitability.
    Steven Tobochnik, Maria Kristina C Dorotan, Hia S Ghosh, Emily Lapinskas, Jayne Vogelzang, David A Reardon, Keith L Ligon, Wenya Linda Bi, Stelios M Smirnakis, Jong Woo Lee.
       BACKGROUND: Distinct genetic alterations determine glioma aggressiveness, however the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures over the course of disease is uncertain. This study aimed to identify tumor somatic mutation profiles associated with clinically significant hyperexcitability.
    METHODS: A single center cohort of adults with WHO grades 1-4 glioma and targeted exome sequencing (n=1716) was analyzed and cross-referenced with a validated EEG database to identify the subset of individuals who underwent continuous EEG monitoring (n=206). Hyperexcitability was defined by the presence of lateralized periodic discharges and/or electrographic seizures. Cross-validated discriminant analysis models trained exclusively on recurrent somatic mutations were used to identify variants associated with hyperexcitability.
    RESULTS: The distribution of WHO grades and tumor mutational burdens were similar between patients with and without hyperexcitability. Discriminant analysis models classified the presence or absence of EEG hyperexcitability with an overall accuracy of 70.9%, regardless of IDH1 R132H inclusion. Predictive variants included nonsense mutations in ATRX and TP53, indel mutations in RBBP8 and CREBBP, and nonsynonymous missense mutations with predicted damaging consequences in EGFR, KRAS, PIK3CA, TP53, and USP28. This profile improved estimates of hyperexcitability in multivariate analysis controlling for age, sex, tumor location, integrated pathologic diagnosis, recurrence status, and pre-operative epilepsy. Predicted somatic mutation variants were over-represented in patients with hyperexcitability compared to individuals without hyperexcitability and those who did not undergo continuous EEG.
    CONCLUSIONS: These findings implicate diverse glioma somatic mutations in cancer genes associated with peritumoral hyperexcitability. Tumor genetic profiling may facilitate glioma-related epilepsy prognostication and management.
    Keywords:  Brain tumor; Electroencephalography; Epilepsy; Glioma; Somatic mutation
    DOI:  https://doi.org/10.1093/neuonc/noad176
  10. Cancer Discov. 2023 Sep 13. OF1
    Microdevice Provides Drug Response Readouts In Situ.
      A tiny drug-eluting device that sits in a brain tumor for the duration of a patient's surgery has shown promise as a clinical tool for guiding personalized treatment decisions. A pilot trial in high-grade gliomas found that the device was safe and could reveal early molecular indicators of drug action.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2023-0067
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