bims-malgli 2023-04-02 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2023–04–02
seven papers selected by
Oltea Sampetrean, Keio University

Tumor microenvironment in glioblastoma: Current and emerging concepts.
Hyperpolarized δ-[1- 13C]gluconolactone imaging visualizes response to TERT or GABPB1 targeting therapy for glioblastoma.
Oncogenic Long Non-coding RNA LINC02283 Enhances PDGF Receptor A mediated Signaling and Drives Glioblastoma Tumorigenesis.
Assessing the added value of apparent diffusion coefficient, cerebral blood volume, and radiomic magnetic resonance features for differentiation of pseudoprogression versus true tumor progression in patients with glioblastoma.
Remote neuronal activity drives glioma infiltration via Sema4f.
ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma.
Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation.

Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad009

Tumor microenvironment in glioblastoma: Current and emerging concepts.

Pratibha Sharma, Ashley Aaroe, Jiyong Liang, Vinay K Puduvalli.

  Glioblastoma (GBM) tumor microenvironment (TME) is a highly heterogeneous and complex system, which in addition to cancer cells, consists of various resident brain and immune cells as well as cells in transit through the tumor such as marrow-derived immune cells. The TME is a dynamic environment which is heavily influenced by alterations in cellular composition, cell-to-cell contact and cellular metabolic products as well as other chemical factors, such as pH and oxygen levels. Emerging evidence suggests that GBM cells appear to reprogram their the TME, and hijack microenvironmental elements to facilitate rapid proliferation, invasion, migration, and survival thus generating treatment resistance. GBM cells interact with their microenvironment directly through cell-to-cell by interaction mediated by cell-surface molecules, or indirectly through apocrine or paracrine signaling via cytokines, growth factors, and extracellular vehicles. The recent discovery of neuron-glioma interfaces and neurotransmitter-based interactions has uncovered novel mechanisms that favor tumor cell survival and growth. Here, we review the known and emerging evidence related to the communication between GBM cells and various components of its TME, discuss models for studying the TME and outline current studies targeting components of the TME for therapeutic purposes.

Keywords:  cell–cell communication; electrical coupling; exosome; extracellular matrix; glioblastoma; paracrine signaling; tumor microenvironment

DOI:  https://doi.org/10.1093/noajnl/vdad009
Sci Rep. 2023 Mar 30. 13(1): 5190

Hyperpolarized δ-[1- 13C]gluconolactone imaging visualizes response to TERT or GABPB1 targeting therapy for glioblastoma.

Noriaki Minami, Donghyun Hong, Celine Taglang, Georgios Batsios, Anne Marie Gillespie, Pavithra Viswanath, Nicholas Stevers, Carter J Barger, Joseph F Costello, Sabrina M Ronen.

TERT promoter mutations are a hallmark of glioblastoma (GBM). Accordingly, TERT and GABPB1, a subunit of the upstream mutant TERT promoter transcription factor GABP, are being considered as promising therapeutic targets in GBM. We recently reported that the expression of TERT or GABP1 modulates flux via the pentose phosphate pathway (PPP). Here, we investigated whether 13C magnetic resonance spectroscopy (MRS) of hyperpolarized (HP) δ- [1-13C]gluconolactone can serve to image the reduction in PPP flux following TERT or GABPB1 silencing. We investigated two different human GBM cell lines stably expressing shRNAs targeting TERT or GABPB1, as well as doxycycline-inducible shTERT or shGABPB1cells. MRS studies were performed on live cells and in vivo tumors, and dynamic sets of 13C MR spectra were acquired following injection of HP δ-[1-13C]gluconolactone. HP 6-phosphogluconolactone (6PG), the product of δ-[1-13C]gluconolactone via the PPP, was significantly reduced in TERT or GABPB1-silenced cells or tumors compared to controls in all our models. Furthermore, a positive correlation between TERT expression and 6PG levels was observed. Our data indicate that HP δ-[1-13C]gluconolactone, an imaging tool with translational potential, could serve to monitor TERT expression and its silencing with therapies that target either TERT or GABPB1 in mutant TERT promoter GBM patients.

DOI: https://doi.org/10.1038/s41598-023-32463-1
Neuro Oncol. 2023 Mar 29. pii: noad065. [Epub ahead of print]

Oncogenic Long Non-coding RNA LINC02283 Enhances PDGF Receptor A mediated Signaling and Drives Glioblastoma Tumorigenesis.

Anshika Goenka, Xiao Song, Deanna Tiek, Rebeca Piatniczka Iglesia, Minghui Lu, Chang Zeng, Craig Horbinski, Wei Zhang, Bo Hu, Shi-Yuan Cheng.

   BACKGROUND: Long non-coding RNAs (lncRNAs) regulate the etiology of complex diseases and cancers, including glioblastoma (GBM). However, lncRNA-based therapies are limited because the mechanisms of action of many lncRNAs with their binding partners are not completely understood.
METHODS: We used transcriptomic and genomic data to analyze correlations between LINC02283 and PDGFRA (Platelet derived growth factor receptor A). The biological functions of the novel lncRNA were assessed in vivo using patient-derived glioma stem-like cells (GSCs), and orthotopic GBM xenografts. Immunoblotting (IB), qRT-PCR, RNA pull down, crosslinked RNA immunoprecipitation (CL-RIP), fluorescence in situ hybridization and ASO-mediated knockdown were performed to explore the regulation of LINC02283 on PDGFRA signaling. Expression of LINC02283 in clinical samples was assessed using pathologically diagnosed GBM patient samples.
RESULTS: We identified a novel oncogenic lncRNA, LINC02283, that is highly expressed in the PDGFRA-mutation driven cohort of glioma patients and associated with worse prognosis. LINC02283 gene co-amplifies with the PDGFRA locus and shows high correlation with PDGFRA expression. Deprivation of LINC02283 in GSCs with PDGFRA amplification mutation, attenuated tumorigenicity and enhanced survival in orthotopic GBM xenograft models, while overexpression of LINC02283 in GSCs with wild type-PDGFRA, enhances PDGFRA signaling, and decreases survival. Further, LINC02283 interacts with PDGFRA to enhance its signaling and that of its downstream targets AKT and ERK, thus promoting oncogenesis in GBM.
CONCLUSIONS: Our results provide strong evidence of LINC02283 as a regulator of PDGFRA oncogenic activity and GBM malignancy and support the potential of lncRNAs as possible therapeutic targets.

Keywords:  LncRNA; PDGFRA; co-amplification; glioblastoma; signaling

DOI:  https://doi.org/10.1093/neuonc/noad065
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad016

Assessing the added value of apparent diffusion coefficient, cerebral blood volume, and radiomic magnetic resonance features for differentiation of pseudoprogression versus true tumor progression in patients with glioblastoma.

Riccardo Leone, Hagen Meredig, Martha Foltyn-Dumitru, Felix Sahm, Stefan Hamelmann, Felix Kurz, Tobias Kessler, David Bonekamp, Heinz-Peter Schlemmer, Mikkel Bo Hansen, Wolfgang Wick, Martin Bendszus, Philipp Vollmuth, Gianluca Brugnara.

   Background: Pseudoprogression (PsPD) is a major diagnostic challenge in the follow-up of patients with glioblastoma (GB) after chemoradiotherapy (CRT). Conventional imaging signs and parameters derived from diffusion and perfusion-MRI have yet to prove their reliability in clinical practice for an accurate differential diagnosis. Here, we tested these parameters and combined them with radiomic features (RFs), clinical data, and MGMT promoter methylation status using machine- and deep-learning (DL) models to distinguish PsPD from Progressive disease.
Methods: In a single-center analysis, 105 patients with GB who developed a suspected imaging PsPD in the first 7 months after standard CRT were identified retrospectively. Imaging data included standard MRI anatomical sequences, apparent diffusion coefficient (ADC), and normalized relative cerebral blood volume (nrCBV) maps. Median values (ADC, nrCBV) and RFs (all sequences) were calculated from DL-based tumor segmentations. Generalized linear models with LASSO feature-selection and DL models were built integrating clinical data, MGMT methylation status, median ADC and nrCBV values and RFs.
Results: A model based on clinical data and MGMT methylation status yielded an areas under the receiver operating characteristic curve (AUC) = 0.69 (95% CI 0.55-0.83) for detecting PsPD, and the addition of median ADC and nrCBV values resulted in a nonsignificant increase in performance (AUC = 0.71, 95% CI 0.57-0.85, P = .416). Combining clinical/MGMT information with RFs derived from ADC, nrCBV, and from all available sequences both resulted in significantly (both P < .005) lower model performances, with AUC = 0.52 (0.38-0.66) and AUC = 0.54 (0.40-0.68), respectively. DL imaging models resulted in AUCs ≤ 0.56.
Conclusion: Currently available imaging biomarkers could not reliably differentiate PsPD from true tumor progression in patients with glioblastoma; larger collaborative efforts are needed to build more reliable models.

Keywords:  glioblastoma; machine-learning; perfusion-MRI; pseudoprogression; radiomics

DOI:  https://doi.org/10.1093/noajnl/vdad016
bioRxiv. 2023 Mar 16. pii: 2023.03.15.532832. [Epub ahead of print]

Remote neuronal activity drives glioma infiltration via Sema4f.

Emmet Huang-Hobbs, Yi-Ting Cheng, Yeunjung Ko, Estefania Luna-Figueroa, Brittney Lozzi, Kathryn R Taylor, Malcolm McDonald, Peihao He, Hsiao-Chi Chen, Yuhui Yang, Ehson Maleki, Zhung-Fu Lee, Sanjana Murali, Michael Williamson, Dongjoo Choi, Rachel Curry, James Bayley, Junsung Woo, Ali Jalali, Michelle Monje, Jeffrey L Noebels, Akdes Serin Harmanci, Ganesh Rao, Benjamin Deneen.

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

DOI: https://doi.org/10.1101/2023.03.15.532832
Neuro Oncol. 2023 Mar 27. pii: noad064. [Epub ahead of print]

ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma.

Jia Xie, Teneema Kuriakose, Brandon Bianski, Nathaniel Twarog, Evan Savage, Ke Xu, Xiaoyan Zhu, Chen He, Baranda Hansen, Hong Wang, Anthony High, Yuxin Li, Jerold E Rehg, Heather S Tillman, Burgess B Freeman, Zoran Rankovic, Arzu Onar-Thomas, Yiping Fan, Gang Wu, Junmin Peng, Shondra Miller, Suzanne J Baker, Anang A Shelat, Christopher L Tinkle.

   BACKGROUND: Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG have alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG.
METHODS: We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts.
RESULTS: AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic non-homologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition.
CONCLUSIONS: Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.

Keywords:  ATM; DNA damage response; pediatric brain tumors; radiation therapy

DOI:  https://doi.org/10.1093/neuonc/noad064
Nat Commun. 2023 Mar 27. 14(1): 1694

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation.

An Xu, Mo Liu, Mo-Fan Huang, Yang Zhang, Ruifeng Hu, Julian A Gingold, Ying Liu, Dandan Zhu, Chian-Shiu Chien, Wei-Chen Wang, Zian Liao, Fei Yuan, Chih-Wei Hsu, Jian Tu, Yao Yu, Taylor Rosen, Feng Xiong, Peilin Jia, Yi-Ping Yang, Danielle A Bazer, Ya-Wen Chen, Wenbo Li, Chad D Huff, Jay-Jiguang Zhu, Francesca Aguilo, Shih-Hwa Chiou, Nathan C Boles, Chien-Chen Lai, Mien-Chie Hung, Zhongming Zhao, Eric L Van Nostrand, Ruiying Zhao, Dung-Fang Lee.

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

DOI: https://doi.org/10.1038/s41467-023-37398-9