bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–10–30
eight papers selected by
Oltea Sampetrean, Keio University
  1. Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma.
  2. FOXO3 regulates a common genomic program in aging and glioblastoma stem cells.
  3. Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma.
  4. Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells.
  5. Integrative genomic analysis facilitates precision strategies for glioblastoma treatment.
  6. BAF complex maintains glioma stem cells in pediatric H3K27M-glioma.
  7. Epigenome programing by H3.3K27M mutation creates a dependence of pediatric glioma on SMARCA4.
  8. Bioimaging Nucleic-Acid Aptamers with Different Specificities in Human Glioblastoma Tissues Highlights Tumoral Heterogeneity.
  1. Acta Neuropathol Commun. 2022 Oct 23. 10(1): 151
    Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma.
    Ahmad Joshkon, Emeline Tabouret, Wael Traboulsi, Richard Bachelier, Stéphanie Simoncini, Sandrine Roffino, Carine Jiguet-Jiglaire, Bassam Badran, Benjamin Guillet, Alexandrine Foucault-Bertaud, Aurelie S Leroyer, Françoise Dignat-George, Olivier Chinot, Hussein Fayyad-Kazan, Nathalie Bardin, Marcel Blot-Chabaud.
       RATIONALE: Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis. The U.S. food and drug administration approved the use of the anti-VEGF antibody bevacizumab in recurrent GBM. However, resistance to this treatment is frequent and fails to enhance the overall survival of patients. In this study, we aimed to identify novel mechanism(s) responsible for bevacizumab-resistance in CD146-positive glioblastoma.
    METHODS: The study was performed using sera from GBM patients and human GBM cell lines in culture or xenografted in nude mice.
    RESULTS: We found that an increase in sCD146 concentration in sera of GBM patients after the first cycle of bevacizumab treatment was significantly associated with poor progression free survival and shorter overall survival. Accordingly, in vitro treatment of CD146-positive glioblastoma cells with bevacizumab led to a high sCD146 secretion, inducing cell invasion. These effects were mediated through integrin αvβ3 and were blocked by mucizumab, a novel humanized anti-sCD146 antibody. In vivo, the combination of bevacizumab with mucizumab impeded CD146 + glioblastoma growth and reduced tumor cell dissemination to an extent significantly higher than that observed with bevacizumab alone.
    CONCLUSION: We propose sCD146 to be 1/ an early biomarker to predict and 2/ a potential target to prevent bevacizumab resistance in patients with glioblastoma.
    Keywords:  Bevacizumab; Biomarker; Glioblastoma; Soluble CD146; Therapeutic antibody
    DOI:  https://doi.org/10.1186/s40478-022-01451-3
  2. Aging Cancer. 2021 Dec;2(4): 137-159
    FOXO3 regulates a common genomic program in aging and glioblastoma stem cells.
    Amanda J Audesse, Galina Karashchuk, Zachary A Gardell, Nelli S Lakis, Sun Y Maybury-Lewis, Abigail K Brown, Dena S Leeman, Yee Voan Teo, Nicola Neretti, Douglas C Anthony, Alexander S Brodsky, Ashley E Webb.
       Background: Glioblastoma (GBM) is an aggressive, age-associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown.
    Aims: Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM.
    Methods and results: We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM-derived GSCs. Using RNA-seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3-regulated pathways are associated with altered mitochondrial functions in both aging and GBM.
    Conclusions: This work identifies a FOXO-associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.
    Keywords:  aging; glioma; stem cells; transcriptomics
    DOI:  https://doi.org/10.1002/aac2.12043
  3. Acta Neuropathol Commun. 2022 Oct 23. 10(1): 150
    Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma.
    Guisheng Zhao, Patrick Newbury, Yukitomo Ishi, Eugene Chekalin, Billy Zeng, Benjamin S Glicksberg, Anita Wen, Shreya Paithankar, Takahiro Sasaki, Amreena Suri, Javad Nazarian, Michael E Pacold, Daniel J Brat, Theodore Nicolaides, Bin Chen, Rintaro Hashizume.
      Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.
    Keywords:  Computational approach; Diffuse intrinsic pontine glioma; Drug repurposing; Machine learning; Mycophenolate mofetil
    DOI:  https://doi.org/10.1186/s40478-022-01463-z
  4. Sci Rep. 2022 Oct 22. 12(1): 17729
    Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells.
    Mariana Belén Vera, Olivia Morris-Hanon, Germán Ignacio Nogueiras, Luisina Belén Ripari, Myrian Inés Esquivel, Carolina Perez-Castro, Leonardo Romorini, Gustavo Emilio Sevlever, María Elida Scassa, Guillermo Agustín Videla-Richardson.
      The recurrence of Glioblastoma is partly attributed to the highly resistant subpopulation of glioma stem cells. A novel therapeutic approach focuses on restoring apoptotic programs in these cancer stem cells, as they are often deregulated. BH3-mimetics, targeting anti-apoptotic Bcl-2 family members, are emerging as promising compounds to sensitize cancer cells to antineoplastic treatments. Herein, we determined that the most abundantly expressed anti-apoptotic Bcl-2 family members, Bcl-xL and Mcl-1, are the most relevant in regulating patient-derived glioma stem cell survival. We exposed these cells to routinely used chemotherapeutic drugs and BH3-mimetics (ABT-263, WEHI-539, and S63845). We observed that the combination of BH3-mimetics targeting Bcl-xL with chemotherapeutic agents caused a marked increase in cell death and that this sensitivity to Bcl-xL inhibition correlated with Noxa expression levels. Interestingly, whereas co-targeting Bcl-xL and Mcl-1 led to massive cell death in all tested cell lines, down-regulation of Noxa promoted cell survival only in cell lines expressing higher levels of this BH3-only. Therefore, in glioma stem cells, the efficacy of Bcl-xL inhibition is closely associated with Mcl-1 activity and Noxa expression. Hence, a potentially effective strategy would consist of combining Bcl-xL inhibitors with chemotherapeutic agents capable of inducing Noxa, taking advantage of this pro-apoptotic factor.
    DOI:  https://doi.org/10.1038/s41598-022-20910-4
  5. iScience. 2022 Nov 18. 25(11): 105276
    Integrative genomic analysis facilitates precision strategies for glioblastoma treatment.
    Danyang Chen, Zhicheng Liu, Jingxuan Wang, Chen Yang, Chao Pan, Yingxin Tang, Ping Zhang, Na Liu, Gaigai Li, Yan Li, Zhuojin Wu, Feng Xia, Cuntai Zhang, Hao Nie, Zhouping Tang.
      Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a dismal prognosis. Currently, the standard treatments for GBM rarely achieve satisfactory results, which means that current treatments are not individualized and precise enough. In this study, a multiomics-based GBM classification was established and three subclasses (GPA, GPB, and GPC) were identified, which have different molecular features both in bulk samples and at single-cell resolution. A robust GBM poor prognostic signature (GPS) score model was then developed using machine learning method, manifesting an excellent ability to predict the survival of GBM. NVP-BEZ235, GDC-0980, dasatinib and XL765 were ultimately identified to have subclass-specific efficacy targeting patients with a high risk of poor prognosis. Furthermore, the GBM classification and GPS score model could be considered as potential biomarkers for immunotherapy response. In summary, an integrative genomic analysis was conducted to advance individual-based therapies in GBM.
    Keywords:  Artificial intelligence; Cancer; Cancer systems biology; Omics
    DOI:  https://doi.org/10.1016/j.isci.2022.105276
  6. Cancer Discov. 2022 Oct 28. pii: CD-21-1491. [Epub ahead of print]
    BAF complex maintains glioma stem cells in pediatric H3K27M-glioma.
    Eshini Panditharatna, Joana G Marques, Tingjian Wang, Maria C Trissal, Ilon Liu, Li Jiang, Alexander Beck, Andrew Groves, Neekesh V Dharia, Deyao Li, Samantha E Hoffman, Guillaume Kugener, McKenzie L Shaw, Hafsa M Mire, Olivia A Hack, Joshua M Dempster, Caleb Lareau, Lingling Dai, Logan H Sigua, Michael A Quezada, Ann-Catherine J Stanton, Meghan Wyatt, Zohra Kalani, Amy Goodale, Francisca Vazquez, Federica Piccioni, John G Doench, David E Root, Jamie N Anastas, Kristen L Jones, Amy Saur Conway, Sylwia Stopka, Michael S Regan, Yu Liang, Hyuk-Soo Seo, Kijun Song, Puspalata Bashyal, William P Jerome, Nathan D Mathewson, Sirano Dhe-Paganon, Mario L Suva, Angel M Carcaboso, Cinzia Lavarino, Jaume Mora, Quang-De Nguyen, Keith L Ligon, Yang Shi, Sameer Agnihotri, Nathalie Y R Agar, Kimberly Stegmaier, Charles D Stiles, Michelle Monje, Todd R Golub, Jun Qi, Mariella G Filbin.
      Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers, refractory to standard of care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell (OPC)-like state, where genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacological suppression opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of BAF complex has translational potential for children with H3K27M-gliomas.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1491
  7. Cancer Discov. 2022 Oct 28. pii: CD-21-1492. [Epub ahead of print]
    Epigenome programing by H3.3K27M mutation creates a dependence of pediatric glioma on SMARCA4.
    Yan Mo, Shoufu Duan, Xu Zhang, Xu Hua, Hui Zhou, Hong-Jian Wei, Jun Watanabe, Nicholas McQuillan, Zhenyi Su, Wei Gu, Cheng-Chia Wu, Christopher R Vakoc, Rintaro Hashizume, Kenneth Chang, Zhiguo Zhang.
      Patients with diffuse midline gliomas-H3K27-altered (DMG) display a dismal prognosis. However, the molecular mechanisms underlying DMG tumorigenesis remain poorly defined. Here we show that SMARCA4, the catalytic subunit of mammalian SWI/SNF chromatin remodeling complex, is essential for the proliferation, migration and invasion of DMG cells and tumor growth in patient-derived DMG xenograft models. SMARCA4 co-localizes with SOX10 at gene regulatory elements (GRE) to control the expression of genes involved in cell growth and extracellular matrix (ECM). Moreover, SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M, a mutation occurring in about 60% DMG tumors. Furthermore, the SMARCA4 occupancy at enhancers marked by both SOX10 and H3K27 acetylation is reduced the most upon depleting the H3.3K27M mutation. Taken together, our results support a model in which epigenome reprogramming by H3.3K27M creates a dependence on SMARCA4-mediated chromatin remodeling to drive gene expression and the pathogenesis of H3.3K27M DMG.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1492
  8. Pharmaceutics. 2022 Sep 20. pii: 1980. [Epub ahead of print]14(10):
    Bioimaging Nucleic-Acid Aptamers with Different Specificities in Human Glioblastoma Tissues Highlights Tumoral Heterogeneity.
    Elisabete Cruz Da Silva, Sophie Foppolo, Benoît Lhermitte, Marina Ingremeau, Hélène Justiniano, Lorraine Klein, Marie-Pierre Chenard, Romain Vauchelles, Basma Abdallah, Maxime Lehmann, Nelly Etienne-Selloum, Monique Dontenwill, Laurence Choulier.
      Nucleic-acid aptamers are of strong interest for diagnosis and therapy. Compared with antibodies, they are smaller, stable upon variations in temperature, easy to modify, and have higher tissue-penetration abilities. However, they have been little described as detection probes in histology studies of human tissue sections. In this study, we performed fluorescence imaging with two aptamers targeting cell-surface receptors EGFR and integrin α5β1, both involved in the aggressiveness of glioblastoma. The aptamers' cell-binding specificities were confirmed using confocal imaging. The affinities of aptamers for glioblastoma cells expressing these receptors were in the 100-300 nM range. The two aptamers were then used to detect EGFR and integrin α5β1 in human glioblastoma tissues and compared with antibody labeling. Our aptafluorescence assays proved to be able to very easily reveal, in a one-step process, not only inter-tumoral glioblastoma heterogeneity (differences observed at the population level) but also intra-tumoral heterogeneity (differences among cells within individual tumors) when aptamers with different specificities were used simultaneously in multiplexing labeling experiments. The discussion also addresses the strengths and limitations of nucleic-acid aptamers for biomarker detection in histology.
    Keywords:  EGFR; cell-surface receptors; detection; glioblastoma; histofluorescence; integrin α5β1; multiplexing; nucleic-acid aptamers
    DOI:  https://doi.org/10.3390/pharmaceutics14101980
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