bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–09–10
ten papers selected by
Oltea Sampetrean, Keio University
  1. Editorial: Recent advances in oncolytic virus therapy for brain tumors.
  2. Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences.
  3. Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone.
  4. Surgical management and outcome of newly diagnosed glioblastoma without contrast enhancement ('low grade appearance') - a report of the RANO resect group.
  5. TFPI2 is key for cancer stem cell-microglia symbiosis in glioblastoma.
  6. Overcoming EGFR inhibitor resistance in Glioblastoma by targeting co-amplified genes.
  7. Intratumoral drug-releasing microdevices allow in situ high-throughput pharmaco phenotyping in patients with gliomas.
  8. Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma.
  9. So Grateful for My X: Sex Chromosomes Drive Differences in Glioblastoma Immunity.
  10. Effective reprogramming of patient-derived M2-polarized glioblastoma-associated microglia/macrophages by treatment with GW2580.
  1. Front Cell Infect Microbiol. 2023 ;13 1271559
    Editorial: Recent advances in oncolytic virus therapy for brain tumors.
    Fatemeh Sana Askari, Alireza Mohebbi, Jianfang Ning, Kazuhiko Kurozumi, Hiroaki Wakimoto.
      
    Keywords:  glioblastoma; glioma; immunotherapy; oncolytic virus; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcimb.2023.1271559
  2. Acta Neuropathol Commun. 2023 Sep 05. 11(1): 143
    Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences.
    Matthew D Wood, Carol Beadling, Tanaya Neff, Steve Moore, Christina A Harrington, Lissa Baird, Christopher Corless.
      Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.
    Keywords:  DNA mismatch repair; High-grade astrocytoma; Hypermutation; Molecular profiling; Pediatric brain tumor
    DOI:  https://doi.org/10.1186/s40478-023-01644-4
  3. bioRxiv. 2023 Aug 21. pii: 2023.08.19.553966. [Epub ahead of print]
    Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone.
    Emily S Norton, Lauren A Whaley, Vanessa K Jones, Mieu M Brooks, Marissa N Russo, Dmytro Morderer, Erik Jessen, Paula Schiapparelli, Andres Ramos-Fresnedo, Natanael Zarco, Anna Carrano, Wilfried Rossoll, Yan W Asmann, TuKiet T Lam, Kaisorn L Chaichana, Panos Z Anastasiadis, Alfredo Quiñones-Hinojosa, Hugo Guerrero-Cázares.
      Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.
    Highlights: Periventricular GBM is more malignant and disrupts neurogenesis in a rodent model.Cell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs.NPCs induce upregulated CTSB expression in GBM, promoting tumor progression.GBM stalls neurogenesis and promotes NPC senescence via CTSB.
    DOI:  https://doi.org/10.1101/2023.08.19.553966
  4. Neuro Oncol. 2023 Sep 04. pii: noad160. [Epub ahead of print]
    Surgical management and outcome of newly diagnosed glioblastoma without contrast enhancement ('low grade appearance') - a report of the RANO resect group.
    Philipp Karschnia, Jorg Dietrich, Francesco Bruno, Antonio Dono, Stephanie T Juenger, Nico Teske, Jacob S Young, Tommaso Sciortino, Levin Häni, Martin van den Bent, Michael Weller, Michael A Vogelbaum, Ramin A Morshed, Alexander F Haddad, Annette M Molinaro, Nitin Tandon, Juergen Beck, Oliver Schnell, Lorenzo Bello, Shawn Hervey-Jumper, Niklas Thon, Stefan J Grau, Yoshua Esquenazi, Roberta Rudà, Susan M Chang, Mitchel S Berger, Daniel P Cahill, Joerg-Christian Tonn.
       BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a 'low grade appearance' on imaging (non-CE glioblastoma). We aimed to (I) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (II) delineate outcome differences between glioblastoma patients with and without contrast enhancement.
    METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between post-operative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement.
    RESULTS: Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller post-operative tumor volumes were associated with more favourable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had more favourable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables.
    CONCLUSIONS: The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favourable outcome.
    Keywords:  WHO 2021; contrast enhancement; extent of resection; glioblastoma; surgery
    DOI:  https://doi.org/10.1093/neuonc/noad160
  5. Nat Immunol. 2023 Sep 04.
    TFPI2 is key for cancer stem cell-microglia symbiosis in glioblastoma.
      
    DOI:  https://doi.org/10.1038/s41590-023-01610-1
  6. Proc Natl Acad Sci U S A. 2023 Sep 19. 120(38): e2312277120
    Overcoming EGFR inhibitor resistance in Glioblastoma by targeting co-amplified genes.
    Ayush Pant, Michael Lim.
      
    DOI:  https://doi.org/10.1073/pnas.2312277120
  7. Sci Transl Med. 2023 Sep 06. 15(712): eadi0069
    Intratumoral drug-releasing microdevices allow in situ high-throughput pharmaco phenotyping in patients with gliomas.
    Pierpaolo Peruzzi, Christine Dominas, Geoffrey Fell, Joshua D Bernstock, Sarah Blitz, Debora Mazzetti, Mykola Zdioruk, Hassan Y Dawood, Daniel V Triggs, Sebastian W Ahn, Sharath K Bhagavatula, Shawn M Davidson, Zuzana Tatarova, Michael Pannell, Kyla Truman, Anna Ball, Maxwell P Gold, Veronika Pister, Ernest Fraenkel, E Antonio Chiocca, Keith L Ligon, Patrick Y Wen, Oliver Jonas.
      The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial (number NCT04135807), we provide first-in-human evidence that drug-releasing intratumoral microdevices (IMDs) can be safely and effectively used to obtain patient-specific, high-throughput molecular and histopathological drug response profiling. These data can complement other strategies to inform the selection of drugs based on their observed antitumor effect in situ. IMDs are integrated into surgical practice during tumor resection and remain in situ only for the duration of the otherwise standard operation (2 to 3 hours). None of the six enrolled patients experienced adverse events related to the IMD, and the exposed tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Analysis of the specimens provided preliminary evidence of the robustness of the readout, compatibility with a wide array of techniques for molecular tissue interrogation, and promising similarities with the available observed clinical-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMDs allows characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor, and without affecting the standard surgical workflow.
    DOI:  https://doi.org/10.1126/scitranslmed.adi0069
  8. Nat Immunol. 2023 Sep 04.
    Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma.
    Lizhi Pang, Madeline Dunterman, Songlin Guo, Fatima Khan, Yang Liu, Erfan Taefi, Atousa Bahrami, Changiz Geula, Wen-Hao Hsu, Craig Horbinski, Charles David James, Peiwen Chen.
      Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.
    DOI:  https://doi.org/10.1038/s41590-023-01605-y
  9. Cancer Discov. 2023 Sep 06. 13(9): 1966-1968
    So Grateful for My X: Sex Chromosomes Drive Differences in Glioblastoma Immunity.
    Elise Alspach.
       SUMMARY: Males are at a greater risk of developing glioblastoma and face poorer prognoses compared with their female counterparts for reasons that are not well understood. Lee and colleagues uncover a role for sex-based differences in CD8+ T-cell function, which adds another layer to our growing understanding that antitumor immunity is not generated equivalently between males and females. See related article by Lee et al., p. 2090 (5).
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0727
  10. Clin Cancer Res. 2023 Sep 08.
    Effective reprogramming of patient-derived M2-polarized glioblastoma-associated microglia/macrophages by treatment with GW2580.
    Valentina Fermi, Rolf Warta, Amélie Wöllner, Catharina Lotsch, Lena Jassowicz, Carmen Rapp, Maximilian Knoll, Gerhard Jungwirth, Christine Jungk, Philip Dao Trong, Andreas von Deimling, Amir Abdollahi, Andreas Unterberg, Christel Herold-Mende.
       PURPOSE: Targeting immunosuppressive and pro-tumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) has great potential to improve patient outcomes. Colony stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprograming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking.
    EXPERIMENTAL DESIGN: CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNAseq, flow cytometry, and cytokine quantification. Functional analyses included iNOS activity, phagocytosis, transmigration, and autologous tumor cell killing assays. Antitumor effects and changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar.
    RESULTS: The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL-6, and IL-10, ERK1/2 and MAPK signaling pathways, while M1-like markers, gene set enrichment indicating activated MHC-II presentation, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming, resulting in impaired tumor cell proliferation. In line with its failure in clinical trials, PLX3397 was ineffective in our analysis.
    CONCLUSION: This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human glioblastoma avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for glioblastoma.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0576
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