bims-malgli 2022-08-07 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–08–07
sixteen papers selected by
Oltea Sampetrean, Keio University

Invasive glioma cells: The malignant pioneers that follow the current.
The multifaceted mechanisms of malignant glioblastoma progression and clinical implications.
ADAR3 activates NF-κB signaling and promotes glioblastoma cell resistance to temozolomide.
A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development.
AAMP is a binding partner of costimulatory human B7-H3.
The Oncolytic Virus G47Δ Shows Efficacy and Safety in Glioblastoma.
Prognostic impact of PDGFRA gain/amplification and MGMT promoter methylation status in patients with IDH wild-type glioblastoma.
Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma.
Intracavity generation of glioma stem cell-specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy.
Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth.
Glioblastoma hijacks neuronal mechanisms for brain invasion.
Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.
AI-based decision support improves reproducibility of tumor response assessment in neuro-oncology: an international multi-reader study.
Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5.
EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.
Eano-Euracan-Sno Guidelines on Circumscribed Astrocytic GLIOMAS, Glioneuronal and Neuronaltumors.

Cell. 2022 Aug 04. pii: S0092-8674(22)00785-1. [Epub ahead of print]185(16): 2846-2848

Invasive glioma cells: The malignant pioneers that follow the current.

Kathryn R Taylor, Michelle Monje.

Glioblastoma is a lethal, diffusely invasive brain cancer that is robustly regulated by the activity of the brain itself, in part through neuron-to-glioma synaptic communication. Venkataramani et al. have conceptually advanced understanding of glioblastoma interactions with neural circuits, demonstrating that conduction of electrochemical signals via neuron-to-glioma synapses drives glioma invasion.

DOI: https://doi.org/10.1016/j.cell.2022.06.033
Cancer Metastasis Rev. 2022 Aug 03.

The multifaceted mechanisms of malignant glioblastoma progression and clinical implications.

Rui Sun, Albert H Kim.

  With the application of high throughput sequencing technologies at single-cell resolution, studies of the tumor microenvironment in glioblastoma, one of the most aggressive and invasive of all cancers, have revealed immense cellular and tissue heterogeneity. A unique extracellular scaffold system adapts to and supports progressive infiltration and migration of tumor cells, which is characterized by altered composition, effector delivery, and mechanical properties. The spatiotemporal interactions between malignant and immune cells generate an immunosuppressive microenvironment, contributing to the failure of effective anti-tumor immune attack. Among the heterogeneous tumor cell subpopulations of glioblastoma, glioma stem cells (GSCs), which exhibit tumorigenic properties and strong invasive capacity, are critical for tumor growth and are believed to contribute to therapeutic resistance and tumor recurrence. Here we discuss the role of extracellular matrix and immune cell populations, major components of the tumor ecosystem in glioblastoma, as well as signaling pathways that regulate GSC maintenance and invasion. We also highlight emerging advances in therapeutic targeting of these components.

Keywords:  Extracellular matrix; Glioblastoma; Glioma stem cell; Immune cell; Invasion; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10555-022-10051-5
Sci Rep. 2022 Aug 03. 12(1): 13362

ADAR3 activates NF-κB signaling and promotes glioblastoma cell resistance to temozolomide.

Reshma Raghava Kurup, Eimile K Oakes, Pranathi Vadlamani, Obi Nwosu, Pranav Danthi, Heather A Hundley.

The RNA binding protein ADAR3 is expressed exclusively in the brain and reported to have elevated expression in tumors of patients suffering from glioblastoma compared to adjacent brain tissue. Yet, other studies have indicated that glioblastoma tumors exhibit hemizygous deletions of the genomic region encompassing ADAR3 (10p15.3). As the molecular and cellular consequences of altered ADAR3 expression are largely unknown, here we directly examined the impacts of elevated ADAR3 in a glioblastoma cell line model. Transcriptome-wide sequencing revealed 641 differentially expressed genes between control and ADAR3-expressing U87-MG glioblastoma cells. A vast majority of these genes belong to pathways involved in glioblastoma progression and are regulated by NF-κB signaling. Biochemical and molecular analysis indicated that ADAR3-expressing U87-MG cells exhibit increased NF-κB activation, and treatment with an NF-κB inhibitor abrogated the impacts of ADAR3 on gene expression. Similarly, we found that increased cell survival of ADAR3-expressing cells to temozolomide, the preferred chemotherapeutic for glioblastoma, was due to increased NF-κB activity. Aberrant constitutive NF-κB activation is a common event in glioblastoma and can impact both tumor progression and resistance to treatment. Our results suggest that elevated ADAR3 promotes NF-κB activation and a gene expression program that provides a growth advantage to glioblastoma cells.

DOI: https://doi.org/10.1038/s41598-022-17559-4
Sci Adv. 2022 Aug 05. 8(31): eabn3986

A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development.

Valerio Benedetti, Federica Banfi, Mattia Zaghi, Raquel Moll-Diaz, Luca Massimino, Laura Argelich, Edoardo Bellini, Simone Bido, Sharon Muggeo, Gabriele Ordazzo, Giuseppina Mastrototaro, Matteo Moneta, Alessandro Sessa, Vania Broccoli.

Current therapies remain unsatisfactory in preventing the recurrence of glioblastoma multiforme (GBM), which leads to poor patient survival. By rational engineering of the transcription factor SOX2, a key promoter of GBM malignancy, together with the Kruppel-associated box and DNA methyltransferase3A/L catalytic domains, we generated a synthetic repressor named SOX2 epigenetic silencer (SES), which induces the transcriptional silencing of its original targets. By doing so, SES kills both glioma cell lines and patient-derived cancer stem cells in vitro and in vivo. SES expression, through local viral delivery in mouse xenografts, induces strong regression of human tumors and survival rescue. Conversely, SES is not harmful to neurons and glia, also thanks to a minimal promoter that restricts its expression in mitotically active cells, rarely present in the brain parenchyma. Collectively, SES produces a significant silencing of a large fraction of the SOX2 transcriptional network, achieving high levels of efficacy in repressing aggressive brain tumors.

DOI: https://doi.org/10.1126/sciadv.abn3986
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac098

AAMP is a binding partner of costimulatory human B7-H3.

Sara Ciprut, Anne Berberich, Maximilian Knoll, Stefan Pusch, Dirk Hoffmann, Jennifer Furkel, Aoife Ward Gahlawat, Lena Kahlert-Konzelamnn, Felix Sahm, Uwe Warnken, Martin Winter, Martina Schnölzer, Sonja Pusch, Andreas von Deimling, Amir Abdollahi, Wolfgang Wick, Dieter Lemke.

   Background: Targeted immunotherapies are of growing interest in the treatment of various cancers. B7 homolog 3 protein (B7-H3), a member of the co-stimulatory/-inhibitory B7-family, exerts immunosuppressive and pro-tumorigenic functions in various cancer types and is under evaluation in ongoing clinical trials. Unfortunately, interaction partner(s) remain unknown which restricts the druggability.
Methods: Aiming to identify potential binding partner(s) of B7-H3, a yeast two-hybrid and a mass spectrometry screen were performed. Potential candidates were evaluated by bimolecular fluorescence complementation (BiFC) assay, co-immunoprecipitation (co-IP), and functionally in a 3H-thymidine proliferation assay of Jurkat cells, a T-cell lineage cell line. Prognostic value of angio-associated migratory cell protein (AAMP) and B7-H3 expression was evaluated in isocitrate dehydrogenase 1 wildtype (IDH1wt) glioblastoma (GBM) patients from The Cancer Genome Atlas (TCGA)-GBM cohort.
Results: Of the screening candidates, CD164, AAMP, PTPRA, and SLAMF7 could be substantiated via BiFC. AAMP binding could be further confirmed via co-IP and on a functional level. AAMP was ubiquitously expressed in glioma cells, immune cells, and glioma tissue, but did not correlate with glioma grade. Finally, an interaction between AAMP and B7-H3 could be observed on expression level, hinting toward a combined synergistic effect.
Conclusions: AAMP was identified as a novel interaction partner of B7-H3, opening new possibilities to create a targeted therapy against the pro-tumorigenic costimulatory protein B7-H3.

Keywords:  brain tumor; glioblastoma; immune therapy; precision medicine; targeted therapy

DOI:  https://doi.org/10.1093/noajnl/vdac098
Cancer Discov. 2022 Aug 05. OF1

The Oncolytic Virus G47Δ Shows Efficacy and Safety in Glioblastoma.

Survival benefit and a manageable safety profile were observed with G47Δ in patients with glioblastoma.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-139
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac097

Prognostic impact of PDGFRA gain/amplification and MGMT promoter methylation status in patients with IDH wild-type glioblastoma.

Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Ryosuke Otsuji, Taiji Hamada, Kei Matsuo, Mari Kirishima, Nobuhiro Hata, Ryosuke Hanaya, Akihide Tanimoto, Koji Yoshimoto.

   Background: Platelet-derived growth factor receptor alpha (PDGFRA) is the second most frequently mutated tyrosine kinase receptor in glioblastoma (GBM). However, the prognostic impact of PDGFRA amplification on GBM patients remains unclear. Herein, we evaluated this impact by retrospectively analyzing outcomes of patients with IDH wild-type GBM.
Methods: Using a custom-made oncopanel, we evaluated PDGFRA gain/amplification in 107 GBM samples harboring wild-type IDH, along with MGMT promoter (MGMTp) methylation status.
Results: We detected PDGFRA gain/amplification in 31 samples (29.0%). PDGFRA gain/amplification predicted poor prognosis (P = .003). Compared to unamplified PDGFRA, PDGFRA gain/amplification in GBM was associated with higher patient age (P = .031), higher Ki-67 score (P = .019), and lower extent of surgical resection (P = .033). Unmethylated MGMTp also predicted poor prognosis (P = .005). As PDGFRA gain/amplification and unmethylated MGMTp were independent factors for poor prognosis in multivariate analyses, we grouped GBM cases based on PDGFRA and MGMTp status: poor (PDGFRA gain/amplification and unmethylated MGMTp), intermediate (PDGFRA gain/amplification or unmethylated MGMTp), and good (PDGFRA intact and methylated MGMTp) prognosis. The Kaplan-Meier survival analysis indicated that these groups significantly correlated with the OS of GBM patients (P < .001).
Conclusions: Here we report that PDGFRA gain/amplification is a predictor of poor prognosis in IDH wild-type GBM. Combining PDGFRA gain/amplification with MGMTp methylation status improves individual prognosis prediction in patients with IDH wild-type GBM.

Keywords:  IDH wild-type; MGMTp; PDGFRA gain/ amplification; glioblastoma; prognostic markers

DOI:  https://doi.org/10.1093/noajnl/vdac097
Commun Biol. 2022 Aug 02. 5(1): 781

Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma.

Lauren Broestl, Nicole M Warrington, Lucia Grandison, Tamara Abou-Antoun, Olivia Tung, Saraswati Shenoy, Miranda M Tallman, Gina Rhee, Wei Yang, Jasmin Sponagel, Lihua Yang, Najla Kfoury-Beaumont, Cameron M Hill, Sulaiman A Qanni, Diane D Mao, Albert H Kim, Sheila A Stewart, Monica Venere, Jingqin Luo, Joshua B Rubin.

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine astrocytes, as well as patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned during early development by gonadal sex. These data provide a rationale for the further study of sex differences in radiation response and how senescence might be enhanced for radiation sensitization. The determination that p21 and gonadal sex are required for sex differences in radiation response will serve as a foundation for these future mechanistic studies.

DOI: https://doi.org/10.1038/s42003-022-03743-9
Sci Transl Med. 2022 Aug 03. 14(656): eabn1128

Intracavity generation of glioma stem cell-specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy.

Chen Chen, Weiqiang Jing, Yu Chen, Ganyu Wang, Mohnad Abdalla, Lin Gao, Maosen Han, Chongdeng Shi, Anning Li, Peng Sun, Xin Jiang, Zhenmei Yang, Shengchang Zhang, Jing Zhang, Chunwei Tang, Ying Liu, Rui Zhang, Fengbo Xu, Baixiang Dong, Xueen Li, Minglu Liu, Bangming Qiang, Yanhua Sun, Xia Wei, Jun Li, Quanyin Hu, Xinyi Jiang.

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene-laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient-derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell-specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.

DOI: https://doi.org/10.1126/scitranslmed.abn1128
Commun Biol. 2022 Aug 02. 5(1): 780

Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth.

Rossella Delle Donne, Rosa Iannucci, Laura Rinaldi, Luca Roberto, Maria A Oliva, Emanuela Senatore, Domenica Borzacchiello, Luca Lignitto, Giorgio Giurato, Francesca Rizzo, Assunta Sellitto, Francesco Chiuso, Salvatore Castaldo, Giovanni Scala, Virginia Campani, Valeria Nele, Giuseppe De Rosa, Chiara D'Ambrosio, Corrado Garbi, Andrea Scaloni, Alessandro Weisz, Concetta Ambrosino, Antonella Arcella, Antonio Feliciello.

Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumor in the adult population; its high recurrence rate and resistance to current therapeutics urgently demand a better therapy. Regulation of protein stability by the ubiquitin proteasome system (UPS) represents an important control mechanism of cell growth. UPS deregulation is mechanistically linked to the development and progression of a variety of human cancers, including GBM. Thus, the UPS represents a potentially valuable target for GBM treatment. Using an integrated approach that includes proteomics, transcriptomics and metabolic profiling, we identify praja2, a RING E3 ubiquitin ligase, as the key component of a signaling network that regulates GBM cell growth and metabolism. Praja2 is preferentially expressed in primary GBM lesions expressing the wild-type isocitrate dehydrogenase 1 gene (IDH1). Mechanistically, we found that praja2 ubiquitylates and degrades the kinase suppressor of Ras 2 (KSR2). As a consequence, praja2 restrains the activity of downstream AMP-dependent protein kinase in GBM cells and attenuates the oxidative metabolism. Delivery in the brain of siRNA targeting praja2 by transferrin-targeted self-assembling nanoparticles (SANPs) prevented KSR2 degradation and inhibited GBM growth, reducing the size of the tumor and prolonging the survival rate of treated mice. These data identify praja2 as an essential regulator of cancer cell metabolism, and as a potential therapeutic target to suppress GBM growth.

DOI: https://doi.org/10.1038/s42003-022-03639-8
Cell. 2022 Aug 04. pii: S0092-8674(22)00847-9. [Epub ahead of print]185(16): 2899-2917.e31

Glioblastoma hijacks neuronal mechanisms for brain invasion.

Varun Venkataramani, Yvonne Yang, Marc Cicero Schubert, Ekin Reyhan, Svenja Kristin Tetzlaff, Niklas Wißmann, Michael Botz, Stella Judith Soyka, Carlo Antonio Beretta, Rangel Lyubomirov Pramatarov, Laura Fankhauser, Luciano Garofano, Alexander Freudenberg, Julia Wagner, Dimitar Ivanov Tanev, Miriam Ratliff, Ruifan Xie, Tobias Kessler, Dirk C Hoffmann, Ling Hai, Yvette Dörflinger, Simone Hoppe, Yahaya A Yabo, Anna Golebiewska, Simone P Niclou, Felix Sahm, Anna Lasorella, Martin Slowik, Leif Döring, Antonio Iavarone, Wolfgang Wick, Thomas Kuner, Frank Winkler.

  Glioblastomas are incurable tumors infiltrating the brain. A subpopulation of glioblastoma cells forms a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs). Other subpopulations appear unconnected, and their biological role remains unclear. Here, we demonstrate that whole-brain colonization is fueled by glioblastoma cells that lack connections with other tumor cells and astrocytes yet receive synaptic input from neurons. This subpopulation corresponds to neuronal and neural-progenitor-like tumor cell states, as defined by single-cell transcriptomics, both in mouse models and in the human disease. Tumor cell invasion resembled neuronal migration mechanisms and adopted a Lévy-like movement pattern of probing the environment. Neuronal activity induced complex calcium signals in glioblastoma cells followed by the de novo formation of TMs and increased invasion speed. Collectively, superimposing molecular and functional single-cell data revealed that neuronal mechanisms govern glioblastoma cell invasion on multiple levels. This explains how glioblastoma's dissemination and cellular heterogeneity are closely interlinked.

Keywords:  cancer neuroscience; cell heterogeneity; glioblastoma; glutamatergic synapse; neurogliomal synapses; neuron-tumor interaction; tumor cell networks; tumor microtubes

DOI:  https://doi.org/10.1016/j.cell.2022.06.054
Proc Natl Acad Sci U S A. 2022 Aug 09. 119(32): e2116289119

Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.

Richard Perryman, Alexander Renziehausen, Hamidreza Shaye, Androniki D Kostagianni, Antonis D Tsiailanis, Thomas Thorne, Maria V Chatziathanasiadou, Gregory B Sivolapenko, Mohamed Ahmed El Mubarak, Gye Won Han, Barbara Zarzycka, Vsevolod Katritch, Guillaume Lebon, Cristiana Lo Nigro, Laura Lattanzio, Sophie V Morse, James J Choi, Kevin O'Neill, Zoi Kanaki, Apostolos Klinakis, Tim Crook, Vadim Cherezov, Andreas G Tzakos, Nelofer Syed.

  Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.

Keywords:  angiotensin II; glioblastoma; renin angiotensin system

DOI:  https://doi.org/10.1073/pnas.2116289119
Neuro Oncol. 2022 Aug 02. pii: noac189. [Epub ahead of print]

AI-based decision support improves reproducibility of tumor response assessment in neuro-oncology: an international multi-reader study.

Philipp Vollmuth, Martha Foltyn, Raymond Y Huang, Norbert Galldiks, Jens Petersen, Fabian Isensee, Martin J van den Bent, Frederik Barkhof, Ji Eun Park, Yae Won Park, Sung Soo Ahn, Gianluca Brugnara, Hagen Meredig, Rajan Jain, Marion Smits, Whitney B Pope, Klaus Maier-Hein, Michael Weller, Patrick Y Wen, Wolfgang Wick, Martin Bendszus.

   BACKGROUND: To assess whether AI-based decision support allows more reproducible and standardized assessment of treatment response on MRI in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden using the RANO criteria.
METHODS: A series of 30 patients (15 lower-grade gliomas, 15 glioblastoma) with availability of consecutive MRI scans was selected. The time to progression (TTP) on MRI was separately evaluated for each patient by 15 investigators over two rounds. In the 1 st round the TTP was evaluated based on the RANO-criteria, whereas in the 2 nd round the TTP was evaluated by incorporating additional information from AI-enhanced MRI-sequences depicting the longitudinal changes in tumor volumes. The agreement of the TTP-measurements between investigators was evaluated using concordance correlation coefficients (CCC) with confidence intervals (CI) and p-values obtained using bootstrap resampling.
RESULTS: The CCC of TTP-measurements between investigators was 0.77 (95%CI=0.69,0.88) with RANO alone and increased to 0.91 (95%CI=0.82,0.95) with AI-based decision support (p=0.005). This effect was significantly greater (p=0.008) for patients with lower-grade gliomas (CCC=0.70 [95%CI=0.56,0.85] without vs. 0.90 [95%CI=0.76,0.95] with AI-based decision support) as compared to glioblastoma (CCC=0.83 [95%CI=0.75,0.92] without vs. 0.86 [95%CI=0.78,0.93] with AI-based decision support). Investigators with less years of experience judged the AI-based decision as more helpful (p=0.02).
CONCLUSIONS: AI-based decision support has the potential to yield more reproducible and standardized assessment of treatment response in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden, particularly in patients with lower-grade gliomas. A fully-functional version of this AI-based processing pipeline is provided as open-source (https://github.com/NeuroAI-HD/HD-GLIO-XNAT).

Keywords:  AI-based decision support; RANO; tumor response assessment; tumor volumetry

DOI:  https://doi.org/10.1093/neuonc/noac189
Nat Cancer. 2022 Aug 01.

Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5.

Ye Sun, Kun Yan, Yi Wang, Cheng Xu, Dan Wang, Wei Zhou, Shuning Guo, Yujie Han, Lei Tang, Yanqiu Shao, Shaobo Shan, Qiangfeng C Zhang, Yujie Tang, Liwei Zhang, Qiaoran Xi.

The most lethal subtype of diffuse intrinsic pontine glioma (DIPG) is H3K27M. Although ACVR1 mutations have been implicated in the pathogenesis of this currently incurable disease, the impacts of bone morphogenetic protein (BMP) signaling on more than 60% of H3K27M DIPG carrying ACVR1 wild-type remain unknown. Here we show that BMP ligands exert potent tumor-suppressive effects against H3.3K27M and ACVR1 WT DIPG in a SMAD-dependent manner. Specifically, clinical data revealed that many DIPG tumors have exploited the capacity of CHRDL1 to hijack BMP ligands. We discovered that activation of BMP signaling promotes the exit of DIPG tumor cells from 'prolonged stem-cell-like' state to differentiation by epigenetically regulating CXXC5, which acts as a tumor suppressor and positive regulator of BMP signaling. Beyond showing how BMP signaling impacts DIPG, our study also identified the potent antitumor efficacy of Dacinostat for DIPG. Thus, our study delineates context-dependent features of the BMP signaling pathway in a DIPG subtype.

DOI: https://doi.org/10.1038/s43018-022-00408-8
Nat Cell Biol. 2022 Aug 01.

EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

Gao Guo, Ke Gong, Nicole Beckley, Yue Zhang, Xiaoyao Yang, Rati Chkheidze, Kimmo J Hatanpaa, Tomas Garzon-Muvdi, Prasad Koduru, Arifa Nayab, Jennifer Jenks, Adwait Amod Sathe, Yan Liu, Chao Xing, Shwu-Yuan Wu, Cheng-Ming Chiang, Bipasha Mukherjee, Sandeep Burma, Bryan Wohlfeld, Toral Patel, Bruce Mickey, Kalil Abdullah, Michael Youssef, Edward Pan, David E Gerber, Shulan Tian, Jann N Sarkaria, Samuel K McBrayer, Dawen Zhao, Amyn A Habib.

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

DOI: https://doi.org/10.1038/s41556-022-00962-4
Neuro Oncol. 2022 Aug 01. pii: noac188. [Epub ahead of print]

Eano-Euracan-Sno Guidelines on Circumscribed Astrocytic GLIOMAS, Glioneuronal and Neuronaltumors.

Roberta Rudà, David Capper, Adam D Waldman, Johan Pallud, Giuseppe Minniti, Thomas J Kaley, Eric Bouffet, Ghazaleh Tabatabai, Eleonora Aronica, Asgeir S Jakola, Stefan M Pfister, David Schiff, Andrew B Lassman, David A Solomon, Riccardo Soffietti, Michael Weller, Matthias Preusser, Ahmed Idbaih, Patrick Y Wen, Martin J van den Bent.

  In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, molecular workup is important for differential diagnosis, in particular DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasingly of prognostic and predictive importance. MRI finding are non specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas .Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.

Keywords:  circumscribed astrocytic gliomas; glioneuronal tumors; guideline; neuronal tumors

DOI:  https://doi.org/10.1093/neuonc/noac188