bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–10–16
eightteen papers selected by
Oltea Sampetrean, Keio University
  1. Programmed death ligand 1 gene silencing in murine glioma models reveals cell line-specific modulation of tumor growth in vivo.
  2. Exploiting Radiation Immunostimulatory Effects To Improve Glioblastoma Outcome.
  3. Mass spectrometry imaging discriminates glioblastoma tumor cell subpopulations and different microvascular formations based on their lipid profiles.
  4. Targeting integrin α2 as potential strategy for radiochemosensitization of glioblastoma.
  5. Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities.
  6. Therapeutic Drug-Induced Metabolic Reprogramming in Glioblastoma.
  7. Prediction of response to lomustine-based chemotherapy in glioma patients at recurrence using MRI and FET PET.
  8. A Germline Variant Deregulates MYC Expression in IDH1-Mutant Glioma.
  9. Targeting extracellular matrix remodeling sensitizes glioblastoma to ionizing radiation.
  10. USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5.
  11. HOXA3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression.
  12. Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions.
  13. TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing.
  14. Pathway-based approach reveals differential sensitivity to E2F1 inhibition in glioblastoma.
  15. Metabolic Heterogeneity of Brain Tumor Cells of Proneural and Mesenchymal Origin.
  16. Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide.
  17. A sequential targeting strategy interrupts AKT-driven subclone-mediated progression in glioblastoma.
  18. Vaccination with designed neopeptides induces intratumoral, cross-reactive CD4+ T cell responses in glioblastoma.
  1. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac148
    Programmed death ligand 1 gene silencing in murine glioma models reveals cell line-specific modulation of tumor growth in vivo.
    Evelina Blomberg, Manuela Silginer, Patrick Roth, Michael Weller.
       Background: Glioblastoma is the most common brain tumor in adults and virtually incurable. Therefore, new therapeutic strategies are urgently needed. Immune checkpoint inhibition has not shown activity in various phase III trials and intra- as well as intertumoral expression of programmed death ligand 1 (PD-L1) varies in glioblastoma.
    Methods: We abrogated constitutive PD-L1 gene expression by CRISPR/Cas9 in murine glioma models and characterized the consequences of gene deletion in vitro and in vivo.
    Results: A heterogeneous expression of Pdl1 mRNA and PD-L1 protein was detected in the glioma cell panel in vitro and in vivo. PD-L1, but not PD-L2, was inducible by interferon β and γ. Co-culture with splenocytes induced PD-L1 expression in GL-261 and SMA-560, but not in CT-2A cells, in an interferon γ-dependent manner. Conversely, Pdl1 gene silencing conferred a survival benefit in CT-2A, but not in the other 2 models. Accordingly, PD-L1 antibody prolonged survival in CT-2A glioma-bearing mice. This activity required PD-L1 expression on tumor rather than host cells, and the survival gain mediated by PD-L1 loss was reproduced in immune-deficient RAG-/- mice.
    Conclusions: PD-L1 is expressed and interferon-inducible in murine glioma cell lines. PD-L1 has model-specific roles for tumor growth. Future studies need to determine which subset of glioblastoma patients may benefit from PD-L1 antagonism as part of a multimodality therapeutic approach to glioblastoma.
    Keywords:  PD-L1; glioblastoma; immune checkpoint inhibition; immunosuppression; immunotherapy
    DOI:  https://doi.org/10.1093/noajnl/vdac148
  2. Neuro Oncol. 2022 Oct 14. pii: noac239. [Epub ahead of print]
    Exploiting Radiation Immunostimulatory Effects To Improve Glioblastoma Outcome.
    Hala Awada, François Paris, Claire Pecqueur.
      Cancer treatment protocols depend on tumor type, localization, grade and patient. Despite aggressive treatments, median survival of patients with Glioblastoma (GBM), the most common primary brain tumor in adults, does not exceed 18 months, and all patients eventually relapse. Thus, novel therapeutic approaches are urgently needed. Radiotherapy induces a multitude of alterations within the tumor ecosystem, ultimately modifying the degree of tumor immunogenicity at GBM relapse. The present manuscript reviews the diverse effects of RT radiotherapy on tumors, with a special focus on its immunomodulatory impact to finally discuss how RT could be exploited in GBM treatment through immunotherapy targeting. Indeed, while further experimental and clinical studies are definitively required to successfully translate preclinical results in clinical trials, current studies highlight the therapeutic potential of immunotherapy to uncover novel avenues to fight GBM.
    Keywords:  Glioblastoma; immunomodulation; radiotherapy
    DOI:  https://doi.org/10.1093/neuonc/noac239
  3. Sci Rep. 2022 Oct 12. 12(1): 17069
    Mass spectrometry imaging discriminates glioblastoma tumor cell subpopulations and different microvascular formations based on their lipid profiles.
    Kelly C O'Neill, Evangelos Liapis, Brent T Harris, David S Perlin, Claire L Carter.
      Glioblastoma is a prevalent malignant brain tumor and despite clinical intervention, tumor recurrence is frequent and usually fatal. Genomic investigations have provided a greater understanding of molecular heterogeneity in glioblastoma, yet there are still no curative treatments, and the prognosis has remained unchanged. The aggressive nature of glioblastoma is attributed to the heterogeneity in tumor cell subpopulations and aberrant microvascular proliferation. Ganglioside-directed immunotherapy and membrane lipid therapy have shown efficacy in the treatment of glioblastoma. To truly harness these novel therapeutics and develop a regimen that improves clinical outcome, a greater understanding of the altered lipidomic profiles within the glioblastoma tumor microenvironment is urgently needed. In this work, high resolution mass spectrometry imaging was utilized to investigate lipid heterogeneity in human glioblastoma samples. Data presented offers the first insight into the histology-specific accumulation of lipids involved in cell metabolism and signaling. Cardiolipins, phosphatidylinositol, ceramide-1-phosphate, and gangliosides, including the glioblastoma stem cell marker, GD3, were shown to differentially accumulate in tumor and endothelial cell subpopulations. Conversely, a reduction in sphingomyelins and sulfatides were detected in tumor cell regions. Cellular accumulation for each lipid class was dependent upon their fatty acid residue composition, highlighting the importance of understanding lipid structure-function relationships. Discriminating ions were identified and correlated to histopathology and Ki67 proliferation index. These results identified multiple lipids within the glioblastoma microenvironment that warrant further investigation for the development of predictive biomarkers and lipid-based therapeutics.
    DOI:  https://doi.org/10.1038/s41598-022-22093-4
  4. Neuro Oncol. 2022 Oct 11. pii: noac237. [Epub ahead of print]
    Targeting integrin α2 as potential strategy for radiochemosensitization of glioblastoma.
    Irina Korovina, Anne Vehlow, Achim Temme, Nils Cordes.
       BACKGROUND: Glioblastoma (GBM) is a fast-growing primary brain tumor characterized by high invasiveness and resistance. This results in poor patient survival. Resistance is caused by many factors, including cell-extracellular matrix (ECM) interactions. Here, we addressed the role of adhesion protein integrin α2, which we identified in a high-throughput screen for novel potential targets in GBM cells treated with standard therapy consisting of temozolomide (TMZ) and radiation.
    METHODS: In our study, we used a range of primary/stem-like and established GBM cell models in vitro and in vivo. To identify regulatory mechanisms, we employed high-throughput kinome profiling, Western blotting, immunofluorescence staining, reporter and activity assays.
    RESULTS: Our data showed that integrin α2 is overexpressed in GBM compared to normal brain and, that its deletion causes radiochemosensitization. Similarly, invasion and adhesion were significantly reduced in TMZ-irradiated GBM cell models. Furthermore, we found that integrin α2-knockdown impairs proliferation of GBM cells without affecting DNA damage repair. At the mechanistic level, we found that integrin α2 affects the activity of activating transcription factor 1 (ATF1) and modulates the expression of extracellular signal-regulated kinase 1 (ERK1) regulated by extracellular signals. Finally, we demonstrated that integrin α2-deficiency inhibits tumor growth and thereby prolongs survival of mice with orthotopically growing GBM xenografts.
    CONCLUSIONS: Taken together our data suggest that integrin α2 may be a promising target to overcome GBM resistance to radio- and chemotherapy. Thus, it would be worth evaluating how efficient and safe the adjuvant use of integrin α2 inhibitors is to standard radio(chemo)therapy in GBM.
    Keywords:   ATF1 ; ERK1 ; Glioblastoma ; integrin α2 ; radiochemoresistance
    DOI:  https://doi.org/10.1093/neuonc/noac237
  5. Front Oncol. 2022 ;12 995498
    Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities.
    Amanda L Johnson, John Laterra, Hernando Lopez-Bertoni.
      Despite its growing use in cancer treatment, immunotherapy has been virtually ineffective in clinical trials for gliomas. The inherently cold tumor immune microenvironment (TIME) in gliomas, characterized by a high ratio of pro-tumor to anti-tumor immune cell infiltrates, acts as a seemingly insurmountable barrier to immunotherapy. Glioma stem cells (GSCs) within these tumors are key contributors to this cold TIME, often functioning indirectly through activation and recruitment of pro-tumor immune cell types. Furthermore, drivers of GSC plasticity and heterogeneity (e.g., reprogramming transcription factors, epigenetic modifications) are associated with induction of immunosuppressive cell states. Recent studies have identified GSC-intrinsic mechanisms, including functional mimicry of immune suppressive cell types, as key determinants of anti-tumor immune escape. In this review, we cover recent advancements in our understanding of GSC-intrinsic mechanisms that modulate GSC-TIME interactions and discuss cutting-edge techniques and bioinformatics platforms available to study immune modulation at high cellular resolution with exploration of both malignant (i.e., GSC) and non-malignant (i.e., immune) cell fractions. Finally, we provide insight into the therapeutic opportunities for targeting immunomodulatory GSC-intrinsic mechanisms to potentiate immunotherapy response in gliomas.
    Keywords:  cancer stem cell; cancer therapy; cellular mimicry; immunomodulation; multi omics; single-cell sequencing; spatial analysis
    DOI:  https://doi.org/10.3389/fonc.2022.995498
  6. Cells. 2022 Sep 22. pii: 2956. [Epub ahead of print]11(19):
    Therapeutic Drug-Induced Metabolic Reprogramming in Glioblastoma.
    Trang T T Nguyen, Enyuan Shang, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.
      Glioblastoma WHO IV (GBM), the most common primary brain tumor in adults, is a heterogenous malignancy that displays a reprogrammed metabolism with various fuel sources at its disposal. Tumor cells primarily appear to consume glucose to entertain their anabolic and catabolic metabolism. While less effective for energy production, aerobic glycolysis (Warburg effect) is an effective means to drive biosynthesis of critical molecules required for relentless growth and resistance to cell death. Targeting the Warburg effect may be an effective venue for cancer treatment. However, past and recent evidence highlight that this approach may be limited in scope because GBM cells possess metabolic plasticity that allows them to harness other substrates, which include but are not limited to, fatty acids, amino acids, lactate, and acetate. Here, we review recent key findings in the literature that highlight that GBM cells substantially reprogram their metabolism upon therapy. These studies suggest that blocking glycolysis will yield a concomitant reactivation of oxidative energy pathways and most dominantly beta-oxidation of fatty acids.
    Keywords:  TCA cycle; glioblastoma; glycolysis; metabolism; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.3390/cells11192956
  7. Neuro Oncol. 2022 Oct 10. pii: noac229. [Epub ahead of print]
    Prediction of response to lomustine-based chemotherapy in glioma patients at recurrence using MRI and FET PET.
    Michael M Wollring, Jan-Michael Werner, Elena K Bauer, Caroline Tscherpel, Garry S Ceccon, Philipp Lohmann, Gabriele Stoffels, Christoph Kabbasch, Roland Goldbrunner, Gereon R Fink, Karl-Josef Langen, Norbert Galldiks.
       BACKGROUND: We evaluated O-(2-[ 18F]fluoroethyl)-L-tyrosine (FET) PET and MRI for early response assessment in recurrent glioma patients treated with lomustine-based chemotherapy.
    METHODS: Thirty-six adult patients with WHO CNS grade 3 or 4 gliomas (glioblastoma, 69%) at recurrence (median number of recurrences, 1; range, 1-3) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (not later than two cycles). Tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of new distant hotspots with a mean TBR >1.6 at follow-up, and the dynamic parameter time-to-peak were derived from all FET PET scans. PET parameter thresholds were defined using ROC analyses to predict PFS of ≥6 months and OS of ≥12 months. MRI response assessment was based on RANO criteria. The predictive values of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates.
    RESULTS: After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Relative changes of TBR, MTV, and RANO criteria predicted a significantly longer PFS (all P≤0.002) and OS (all P≤0.045). At follow-up, the occurrence of new distant hotspots (n≥1) predicted a worse outcome, with significantly shorter PFS (P=0.005) and OS (P<0.001). Time-to-peak changes did not predict a significantly longer survival. Multivariate survival analyses revealed that new distant hotspots at follow-up FET PET were most potent in predicting non-response (P<0.001; HR, 8.578).
    CONCLUSIONS: Data suggest that FET PET provides complementary information to RANO criteria for response evaluation of lomustine-based chemotherapy early after treatment initiation.
    Keywords:  CCNU; Glioblastoma; amino acid PET; nitrosourea
    DOI:  https://doi.org/10.1093/neuonc/noac229
  8. Cancer Discov. 2022 Oct 14. OF1
    A Germline Variant Deregulates MYC Expression in IDH1-Mutant Glioma.
      The germline polymorphism rs55705857-G was identified as the causal variant in IDH-mutant glioma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-181
  9. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac147
    Targeting extracellular matrix remodeling sensitizes glioblastoma to ionizing radiation.
    Varsha Thakur, Vijay S Thakur, Brittany Aguila, Tatiana I Slepak, Man Wang, Wei Song, Mohini Konai, Shahriar Mobashery, Mayland Chang, Ayush B Rana, Dazhi Wang, Juliano Tiburcio de Freitas, Sakir Humayun Gultekin, Scott M Welford, Michael E Ivan, Barbara Bedogni.
       Background: The median survival of Glioblastoma multiforme (GBM) patients is 14+ months due to poor responses to surgery and chemoradiation. Means to counteract radiation resistance are therefore highly desirable. We demonstrate the membrane bound matrix metalloproteinase MT1-MMP promotes resistance of GBM to radiation, and that using a selective and brain permeable MT1-MMP inhibitor, (R)-ND336, improved tumor control can be achieved in preclinical studies.
    Methods: Public microarray and RNA-sequencing data were used to determine MT1-MMP relevance in GBM patient survival. Glioma stem-like neurospheres (GSCs) were used for both in vitro and in vivo assays. An affinity resin coupled with proteomics was used to quantify active MT1-MMP in brain tissue of GBM patients. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP and inhibition via the MT1-MMP inhibitor (R)-ND336, were used to assess the role of MT1-MMP in radio-resistance.
    Results: MT1-MMP expression inversely correlated with patient survival. Active MT1-MMP was present in brain tissue of GBM patients but not in normal brain. shRNA- or (R)-ND336-mediated inhibition of MT1-MMP sensitized GSCs to radiation leading to a significant increase in survival of tumor-bearing animals. MT1-MMP depletion reduced invasion via the effector protease MMP2; and increased the cytotoxic response to radiation via induction of replication fork stress and accumulation of double strand breaks (DSBs), making cells more susceptible to genotoxic insult.
    Conclusions: MT1-MMP is pivotal in maintaining replication fork stability. Disruption of MT1-MMP sensitizes cells to radiation and can counteract invasion. (R)-ND336, which efficiently penetrates the brain, is therefore a novel radio-sensitizer in GBM.
    Keywords:  (R)-ND336; GBM; MT1-MMP; radiation resistance; radio-sensitization
    DOI:  https://doi.org/10.1093/noajnl/vdac147
  10. Neuro Oncol. 2022 Oct 14. pii: noac238. [Epub ahead of print]
    USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5.
    Guoqiang Chang, Gloria S Xie, Li Ma, Peng Li, Linlin Li, Hope T Richard.
       BACKGROUND: ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability.
    METHODS: The contribution of deubiquitinating enzymes (DUB) to the fluctuation of ALKBH5 protein expression were globally profiled with western blot analysis. Mass spectrometry and immunoprecipitation were performed to identify the USP36 and ALKBH5 interaction. The effects of USP36 on the stability of ALKBH5 were detected with in vivo and in vitro ubiquitination assays. Cell proliferation assays, neurosphere formation, limited dilution assay, and intracranial tumor growth assays were implemented to assess the collaborative capacities of USP36 and ALKBH5 in tumorigenesis.
    RESULTS: Ubiquitin-specific peptidase 36 (USP36), as a potential ALKBH5-activating DUB, played an essential role in stabilization of ALKBH5 and regulation of ALKBH5 mediated gene expression in glioblastoma. The depletion of USP36 drastically impaired cell proliferation, deteriorated the self-renewal of GSCs and sensitized GSCs to temozolomide (TMZ) treatment. Furthermore, the deletion of USP36 substantially decreased the in vivo tumor growth when monitored by bioluminescence imaging. Our findings indicate that USP36 regulates the protein degradation and expression of ALKBH5, and the USP36-ALKBH5 axis orchestrates glioma tumorigenesis.
    CONCLUSION: Our findings identify USP36 as a DUB of ALKBH5 and its role in glioblastoma progression, which may serve as a potential therapeutic target for glioblastoma treatment.
    Keywords:  ALKBH5; USP36; deubiquitination; glioblastoma stem cells
    DOI:  https://doi.org/10.1093/neuonc/noac238
  11. Neuro Oncol. 2022 Oct 10. pii: noac231. [Epub ahead of print]
    HOXA3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression.
    Rui Yang, Guanghui Zhang, Zhen Dong, Shanshan Wang, Yanping Li, Fuming Lian, Xiaoran Liu, Haibin Li, Xiaonan Wei, Hongjuan Cui.
       BACKGROUND: Alterations in transcriptional regulators of glycolytic metabolism have been implicated in brain tumor growth, but the underlying molecular mechanisms remain poorly understand.
    METHODS: Knockdown and overexpression cells were used to explore the functional roles of HOXA3 in cell proliferation, tumor formation and aerobic glycolysis. Chromatin immunoprecipitation, luciferase assays and western blotting were performed to verify the regulation of HK2 and PKM2 by HOXA3. PLA, Immunoprecipitation and GST pull down assays were used to examine the interaction of HOXA3 and KDM6A.
    RESULTS: We report that transcription factor homeobox A3 (HOXA3), which is aberrantly highly expressed in glioblastoma (GBM) patients and predicts poor prognosis, transcriptionally activates aerobic glycolysis, leading to a significant acceleration in cell proliferation and tumor growth. Mechanically, we identified KDM6A, a lysine-specific demethylase, as an important cooperator of HOXA3 to regulating aerobic glycolysis. HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes, targeting glycolytic genes for transcriptional activation by removing the suppressive histone modification H3K27 trimethylation. Further evidences demonstrate that HOXA3 requires KDM6A for transcriptional activation of aerobic glycolysis and brain tumor growth.
    CONCLUSION: Our findings provide a novel molecular mechanism linking HOXA3-mediated transactivation and KDM6A-coupled H3K27 demethylation in regulating glucose metabolism and GBM progression.
    Keywords:  GBM; HOXA3; KDM6A; aerobic glycolysis; transcriptional activation
    DOI:  https://doi.org/10.1093/neuonc/noac231
  12. Neuro Oncol. 2022 Oct 12. pii: noac207. [Epub ahead of print]
    Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions.
    Julie J Miller, L Nicolas Gonzalez Castro, Samuel McBrayer, Michael Weller, Timothy Cloughesy, Jana Portnow, Ovidiu Andronesi, Jill S Barnholtz-Sloan, Brigitta G Baumert, Mitchell S Berger, Wenya Linda Bi, Ranjit Bindra, Daniel P Cahill, Susan M Chang, Joseph F Costello, Craig Horbinski, Raymond Y Huang, Robert B Jenkins, Keith L Ligon, Ingo K Mellinghoff, L Burt Nabors, Michael Platten, David A Reardon, Diana D Shi, David Schiff, Wolfgang Wick, Hai Yan, Andreas von Deimling, Martin van den Bent, William G Kaelin, Patrick Y Wen.
      Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.
    Keywords:   D-2HG; Isocitrate dehydrogenase (IDH); glioma
    DOI:  https://doi.org/10.1093/neuonc/noac207
  13. Neuro Oncol. 2022 Oct 10. pii: noac233. [Epub ahead of print]
    TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing.
    Engin Demirdizen, Ruslan Al-Ali, Ashwin Narayanan, Xueyuan Sun, Julianna Patricia Varga, Bianca Steffl, Manuela Brom, Damir Krunic, Claudia Schmidt, Gabriele Schmidt, Felix Bestvater, Julian Taranda, Şevin Turcan.
       BACKGROUND: IDH mutant gliomas are grouped into astrocytomas or oligodendrogliomas depending on the co-deletion of chromosome arms 1p and 19q. Although the genomic alterations of IDH mutant gliomas have been well described, transcriptional changes unique to either tumor type have not been fully understood. Here, we identify Tripartite Motif Containing 67 (TRIM67), an E3 ubiquitin ligase with essential roles during neuronal development, as an oncogene distinctly upregulated in oligodendrogliomas.
    METHODS: We used several cell lines, including patient-derived oligodendroglioma tumorspheres, to knockdown or overexpress TRIM67. We coupled high-throughput assays, including RNA sequencing, total lysate-mass spectrometry (MS) and co-immunoprecipitation (co-IP)-MS with functional assays including immunofluorescence (IF) staining, co-IP and western blotting (WB) to assess the in vitro phenotype associated with TRIM67. Patient-derived oligodendroglioma tumorspheres were orthotopically implanted in mice to determine the effect of TRIM67 on tumor growth and survival.
    RESULTS: TRIM67 overexpression alters the abundance of cytoskeletal proteins and induces membrane bleb formation. TRIM67-associated blebbing was reverted with the nonmuscle class II myosin inhibitor blebbistatin and selective ROCK inhibitor fasudil. NOGO-A/Rho GTPase/ROCK2 signaling is altered upon TRIM67 ectopic expression, pointing to the underlying mechanism for TRIM67-induced blebbing. Phenotypically, TRIM67 expression resulted in higher cell motility and reduced cell adherence. In orthotopic implantation models of patient-derived oligodendrogliomas, TRIM67 accelerated tumor growth, reduced overall survival, and led to increased vimentin expression at the tumor margin.
    CONCLUSION: Taken together, our results demonstrate that upregulated TRIM67 induces blebbing-based rounded cell morphology through Rho GTPase/ROCK-mediated signaling thereby contributing to glioma pathogenesis.
    Keywords:  E3 ligase; Rho GTPase signaling; TRIM67; glioma; membrane blebbing; mouse
    DOI:  https://doi.org/10.1093/neuonc/noac233
  14. Cancer Res Commun. 2022 Sep;2(9): 1049-1060
    Pathway-based approach reveals differential sensitivity to E2F1 inhibition in glioblastoma.
    Alvaro G Alvarado, Kaleab Tessema, Sree Deepthi Muthukrishnan, Mackenzie Sober, Riki Kawaguchi, Dan R Laks, Aparna Bhaduri, Vivek Swarup, David A Nathanson, Daniel H Geschwind, Steven A Goldman, Harley I Kornblum.
      Analysis of tumor gene expression is an important approach for the classification and identification of therapeutic vulnerabilities. However, targeting glioblastoma (GBM) based on molecular subtyping has not yet translated into successful therapies. Here, we present an integrative approach based on molecular pathways to expose new potentially actionable targets. We used gene set enrichment analysis (GSEA) to conduct an unsupervised clustering analysis to condense the gene expression data from bulk patient samples and patient-derived gliomasphere lines into new gene signatures. We identified key targets that are predicted to be differentially activated between tumors and were functionally validated in a library of gliomasphere cultures. Resultant cluster-specific gene signatures associated not only with hallmarks of cell cycle and stemness gene expression, but also with cell-type specific markers and different cellular states of GBM. Several upstream regulators, such as PIK3R1 and EBF1 were differentially enriched in cells bearing stem cell like signatures and bear further investigation. We identified the transcription factor E2F1 as a key regulator of tumor cell proliferation and self-renewal in only a subset of gliomasphere cultures predicted to be E2F1 signaling dependent. Our in vivo work also validated the functional significance of E2F1 in tumor formation capacity in the predicted samples. E2F1 inhibition also differentially sensitized E2F1-dependent gliomasphere cultures to radiation treatment. Our findings indicate that this novel approach exploring cancer pathways highlights key therapeutic vulnerabilities for targeting GBM.
    Keywords:  CIP2A; E2F1; Glioblastoma; Molecular targets; Tumoral heterogeneity
    DOI:  https://doi.org/10.1158/2767-9764.crc-22-0003
  15. Int J Mol Sci. 2022 Oct 01. pii: 11629. [Epub ahead of print]23(19):
    Metabolic Heterogeneity of Brain Tumor Cells of Proneural and Mesenchymal Origin.
    Corinna Seliger, Anne-Louise Meyer, Verena Leidgens, Lisa Rauer, Sylvia Moeckel, Birgit Jachnik, Judith Proske, Katja Dettmer, Tanja Rothhammer-Hampl, Leon D Kaulen, Markus J Riemenschneider, Peter J Oefner, Marina Kreutz, Nils-Ole Schmidt, Marsha Merrill, Martin Uhl, Kathrin Renner, Arabel Vollmann-Zwerenz, Martin Proescholdt, Peter Hau.
      Brain-tumor-initiating cells (BTICs) of proneural and mesenchymal origin contribute to the highly malignant phenotype of glioblastoma (GB) and resistance to current therapies. BTICs of different subtypes were challenged with oxidative phosphorylation (OXPHOS) inhibition with metformin to assess the differential effects of metabolic intervention on key resistance features. Whereas mesenchymal BTICs varied according to their invasiveness, they were in general more glycolytic and less responsive to metformin. Proneural BTICs were less invasive, catabolized glucose more via the pentose phosphate pathway, and responded better to metformin. Targeting glycolysis may be a promising approach to inhibit tumor cells of mesenchymal origin, whereas proneural cells are more responsive to OXPHOS inhibition. Future clinical trials exploring metabolic interventions should account for metabolic heterogeneity of brain tumors.
    Keywords:  glioma; metabolism; metformin
    DOI:  https://doi.org/10.3390/ijms231911629
  16. Front Oncol. 2022 ;12 900082
    Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide.
    Alessia Lodi, Renu Pandey, Jennifer Chiou, Ayon Bhattacharya, Shiliang Huang, Xingxin Pan, Brandon Burgman, S Stephen Yi, Stefano Tiziani, Andrew J Brenner.
      Glioblastomas (GBM) are the most common and aggressive form of primary malignant brain tumor in the adult population, and, despite modern therapies, patients often develop recurrent disease, and the disease remains incurable with median survival below 2 years. Resistance to bevacizumab is driven by hypoxia in the tumor and evofosfamide is a hypoxia-activated prodrug, which we tested in a phase 2, dual center (University of Texas Health Science Center in San Antonio and Dana Farber Cancer Institute) clinical trial after bevacizumab failure. Tumor hypoxic volume was quantified by 18F-misonidazole PET. To identify circulating metabolic biomarkers of tumor hypoxia in patients, we used a high-resolution liquid chromatography-mass spectrometry-based approach to profile blood metabolites and their specific enantiomeric forms using untargeted approaches. Moreover, to evaluate early response to treatment, we characterized changes in circulating metabolite levels during treatment with combined bevacizumab and evofosfamide in recurrent GBM after bevacizumab failure. Gamma aminobutyric acid, and glutamic acid as well as its enantiomeric form D-glutamic acid all inversely correlated with tumor hypoxia. Intermediates of the serine synthesis pathway, which is known to be modulated by hypoxia, also correlated with tumor hypoxia (phosphoserine and serine). Moreover, following treatment, lactic acid was modulated by treatment, likely in response to a hypoxia mediated modulation of oxidative vs glycolytic metabolism. In summary, although our results require further validation in larger patients' cohorts, we have identified candidate metabolic biomarkers that could evaluate the extent of tumor hypoxia and predict the benefit of combined bevacizumab and evofosfamide treatment in GBM following bevacizumab failure.
    Keywords:  D-glutamic acid (D-Glu); bevacizumab (BEV); circulating metabolites; enantiomers; evofosfamide (TH-302); glioblastoma (GBM); metabolomics (OMICS)
    DOI:  https://doi.org/10.3389/fonc.2022.900082
  17. Clin Cancer Res. 2022 Oct 14. pii: CCR-22-0611. [Epub ahead of print]
    A sequential targeting strategy interrupts AKT-driven subclone-mediated progression in glioblastoma.
    Sied Kebir, Vivien Ullrich, Pia Berger, Celia Dobersalske, Sarah Langer, Laurèl Rauschenbach, Daniel Trageser, Andreas Till, Franziska K Lorbeer, Anja Wieland, Timo Wilhelm-Buchstab, Ashar Ahmad, Holger Fröhlich, Igor Cima, Shruthi Prasad, Johann Matschke, Verena Jendrossek, Marc Remke, Barbara M Grüner, Alexander Roesch, Jens T Siveke, Christel Herold-Mende, Tobias Blau, Kathy Keyvani, Frank K H van Landeghem, Torsten Pietsch, Jörg Felsberg, Guido Reifenberger, Michael Weller, Ulrich Sure, Oliver Brüstle, Matthias Simon, Martin Glas, Bjorn Scheffler.
       PURPOSE: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly target tumor cells that can survive, adapt, and subclonally expand under primary therapy.
    EXPERIMENTAL DESIGN: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts.
    RESULTS: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide. Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after temozolomide treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of temozolomide. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy.
    CONCLUSION: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to temozolomide therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of temozolomide and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0611
  18. Clin Cancer Res. 2022 Oct 13. pii: CCR-22-1741. [Epub ahead of print]
    Vaccination with designed neopeptides induces intratumoral, cross-reactive CD4+ T cell responses in glioblastoma.
    Jian Wang, Tobias Weiss, Marian C Neidert, Nora C Toussaint, Reza Naghavian, Carla Moreno Sellés, Magdalena Foege, Paula Tomas Ojer, Gioele Medici, Ivan Jelcic, Daniel Schulz, Elisabeth Rushing, Susanne Dettwiler, Barbara Schrörs, Joo Heon Shin, Ron McKay, Catherine J Wu, Andreas Lutterotti, Mireia Sospedra, Holger Moch, Erich F Greiner, Bernd Bodenmiller, Luca Regli, Michael Weller, Patrick Roth, Roland Martin.
       PURPOSE: The low mutational load of some cancers is considered one reason for the difficulties to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutation to enhance their immunogenicity.
    EXPERIMENTAL DESIGN: Exome- and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T cell receptor contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TILs) were characterized in detail both at the bulk and clonal level.
    RESULTS: The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100% respectively of the vaccine peptides. Further, TIL-derived CD4+ T cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor.
    CONCLUSIONS: Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T cell responses in a cold tumor like glioblastoma.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1741
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