bims-malgli 2021-11-28 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2021–11–28
thirteen papers selected by
Oltea Sampetrean, Keio University

BACE1 Inhibition Stimulates Macrophage Phagocytosis of Glioblastoma Cells.
Glioma Cells Acquire Stem-like Characters by Extrinsic Ribosome Stimuli.
Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells.
Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?
Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres.
Protein kinase Cι and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.
Cell-free DNA technologies for the analysis of brain cancer.
Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?
Therapeutic potential of parkin as a tumor suppressor via transcriptional control of cyclins in glioblastoma cell and animal models.
Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.
The Evolving Classification of Diffuse Gliomas: World Health Organization Updates for 2021.
The von Willebrand factor stamps plasmatic extracellular vesicles from glioblastoma patients.
NAD+ bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells.

Cancer Discov. 2021 Nov 24.

BACE1 Inhibition Stimulates Macrophage Phagocytosis of Glioblastoma Cells.

BACE1 inhibition reprograms macrophages to promote their phagocytosis of cancer cells reducing glioblastoma progression.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2021-169
Cells. 2021 Nov 01. pii: 2970. [Epub ahead of print]10(11):

Glioma Cells Acquire Stem-like Characters by Extrinsic Ribosome Stimuli.

Yuki Shirakawa, Kunimasa Ohta, Shunsuke Miyake, Ayumi Kanemaru, Akari Kuwano, Kou Yonemaru, Shota Uchino, Michiko Yamaoka, Yuki Ito, Naofumi Ito, Takuichiro Hide, Naoki Shinojima, Akitake Mukasa, Hideyuki Saito, Hirofumi Jono.

  Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

Keywords:  glioblastoma; ribosomal protein S6; ribosome; ribosome-induced cancer cell spheroid

DOI:  https://doi.org/10.3390/cells10112970
Cells. 2021 Nov 21. pii: 3258. [Epub ahead of print]10(11):

Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells.

Elisabete Cruz Da Silva, Laurence Choulier, Jessica Thevenard-Devy, Christophe Schneider, Philippe Carl, Philippe Rondé, Stéphane Dedieu, Maxime Lehmann.

  EGFR (epidermal growth factor receptor), a member of the ErbB tyrosine kinase receptor family, is a clinical therapeutic target in numerous solid tumours. EGFR overexpression in glioblastoma (GBM) drives cell invasion and tumour progression. However, clinical trials were disappointing, and a molecular basis to explain these poor results is still missing. EGFR endocytosis and membrane trafficking, which tightly regulate EGFR oncosignaling, are often dysregulated in glioma. In a previous work, we showed that EGFR tyrosine kinase inhibitors, such as gefitinib, lead to enhanced EGFR endocytosis into fused early endosomes. Here, using pharmacological inhibitors, siRNA-mediated silencing, or expression of mutant proteins, we showed that dynamin 2 (DNM2), the small GTPase Rab5 and the endocytosis receptor LDL receptor-related protein 1 (LRP-1), contribute significantly to gefitinib-mediated EGFR endocytosis in glioma cells. Importantly, we showed that inhibition of DNM2 or LRP-1 also decreased glioma cell responsiveness to gefitinib during cell evasion from tumour spheroids. By highlighting the contribution of endocytosis proteins in the activity of gefitinib on glioma cells, this study suggests that endocytosis and membrane trafficking might be an attractive therapeutic target to improve GBM treatment.

Keywords:  cell invasion; glioblastoma; membrane trafficking; tyrosine kinase inhibitors

DOI:  https://doi.org/10.3390/cells10113258
Cancers (Basel). 2021 Nov 18. pii: 5799. [Epub ahead of print]13(22):

Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?

Paula Aldaz, Imanol Arozarena.

  Glioblastoma (GBM) is the most common and lethal form of malignant brain tumor. GBM patients normally undergo surgery plus adjuvant radiotherapy followed by chemotherapy. Numerous studies into the molecular events driving GBM highlight the central role played by the Epidermal Growth Factor Receptor (EGFR), as well as the Platelet-derived Growth Factor Receptors PDGFRA and PDGFRB in tumor initiation and progression. Despite strong preclinical evidence for the therapeutic potential of tyrosine kinase inhibitors (TKIs) that target EGFR, PDGFRs, and other tyrosine kinases, clinical trials performed during the last 20 years have not led to the desired therapeutic breakthrough for GBM patients. While clinical trials are still ongoing, in the medical community there is the perception of TKIs as a lost opportunity in the fight against GBM. In this article, we review the scientific rationale for the use of TKIs targeting glioma drivers. We critically analyze the potential causes for the failure of TKIs in the treatment of GBM, and we propose alternative approaches to the clinical evaluation of TKIs in GBM patients.

Keywords:  glioblastoma; receptor tyrosine kinase; targeted therapy; tyrosine kinase inhibitors

DOI:  https://doi.org/10.3390/cancers13225799
Biology (Basel). 2021 Nov 09. pii: 1157. [Epub ahead of print]10(11):

Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres.

Martina Giambra, Eleonora Messuti, Andrea Di Cristofori, Clarissa Cavandoli, Raffaele Bruno, Raffaella Buonanno, Matilde Marzorati, Melissa Zambuto, Virginia Rodriguez-Menendez, Serena Redaelli, Carlo Giussani, Angela Bentivegna.

  Glioblastoma is an extremely heterogeneous disease. Treatment failure and tumor recurrence primarily reflect the presence in the tumor core (TC) of the glioma stem cells (GSCs), and secondly the contribution, still to be defined, of the peritumoral brain zone (PBZ). Using the array-CGH platform, we deepened the genomic knowledge about the different components of GBM and we identified new specific biomarkers useful for new therapies. We firstly investigated the genomic profile of 20 TCs of GBM; then, for 14 cases and 7 cases, respectively, we compared these genomic profiles with those of the related GSC cultures and PBZ biopsies. The analysis on 20 TCs confirmed the intertumoral heterogeneity and a high percentage of copy number alterations (CNAs) in GBM canonical pathways. Comparing the genomic profiles of 14 TC-GSC pairs, we evidenced a robust similarity among the two samples of each patient. The shared imbalanced genes are related to the development and progression of cancer and in metabolic pathways, as shown by bioinformatic analysis using DAVID. Finally, the comparison between 7 TC-PBZ pairs leads to the identification of PBZ-unique alterations that require further investigation.

Keywords:  GBM; array-CGH; copy number alterations; genomic profile; glioblastoma; glioma stem cell; peritumoral brain zone

DOI:  https://doi.org/10.3390/biology10111157
Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01540-0. [Epub ahead of print]37(8): 110054

Protein kinase Cι and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities.

Rajappa S Kenchappa, Yi Liu, Michael G Argenziano, Matei A Banu, Ann C Mladek, Rita West, Amanda Luu, Alfredo Quiñones-Hinojosa, Dolores Hambardzumyan, Verline Justilien, Michael Leitges, Jann N Sarkaria, Peter A Sims, Peter Canoll, Nicole R Murray, Alan P Fields, Steven S Rosenfeld.

  We report that atypical protein kinase Cι (PKCι) is an oncogenic driver of glioblastoma (GBM). Deletion or inhibition of PKCι significantly impairs tumor growth and prolongs survival in murine GBM models. GBM cells expressing elevated PKCι signaling are sensitive to PKCι inhibitors, whereas those expressing low PKCι signaling exhibit active SRC signaling and sensitivity to SRC inhibitors. Resistance to the PKCι inhibitor auranofin is associated with activated SRC signaling and response to a SRC inhibitor, whereas resistance to a SRC inhibitor is associated with activated PKCι signaling and sensitivity to auranofin. Interestingly, PKCι- and SRC-dependent cells often co-exist in individual GBM tumors, and treatment of GBM-bearing mice with combined auranofin and SRC inhibitor prolongs survival beyond either drug alone. Thus, we identify PKCι and SRC signaling as distinct therapeutic vulnerabilities that are directly translatable into an improved treatment for GBM.

Keywords:  SRC; glioblastoma; kinase inhibitor; protein kinase C iota

DOI:  https://doi.org/10.1016/j.celrep.2021.110054
Br J Cancer. 2021 Nov 22.

Cell-free DNA technologies for the analysis of brain cancer.

Richard Mair, Florent Mouliere.

Survival for glioma patients has shown minimal improvement over the past 20 years. The ability to detect and monitor gliomas relies primarily upon imaging technologies that lack sensitivity and specificity, especially during the post-surgical treatment phase. Treatment-response monitoring with an effective liquid-biopsy paradigm may also provide the most facile clinical scenario for liquid-biopsy integration into brain-tumour care. Conceptually, liquid biopsy is advantageous when compared with both tissue sampling (less invasive) and imaging (more sensitive and specific), but is hampered by technical and biological problems. These problems predominantly relate to low concentrations of tumour-derived DNA in the bloodstream of glioma patients. In this review, we highlight methods by which the neuro-oncological scientific and clinical communities have attempted to circumvent this limitation. The use of novel biological, technological and computational approaches will be explored. The utility of alternate bio-fluids, tumour-guided sequencing, epigenomic and fragmentomic methods may eventually be leveraged to provide the biological and technological means to unlock a wide range of clinical applications for liquid biopsy in glioma.

DOI: https://doi.org/10.1038/s41416-021-01594-5
Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab133

Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?

Anna Qin, Anna Musket, Phillip R Musich, John B Schweitzer, Qian Xie.

  Glioblastoma (GBM) is the most malignant primary brain tumor without effective therapies. Since bevacizumab was FDA approved for targeting vascular endothelial growth factor receptor 2 (VEGFR2) in adult patients with recurrent GBM, targeted therapy against receptor tyrosine kinases (RTKs) has become a new avenue for GBM therapeutics. In addition to VEGFR, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) are major RTK targets. However, results from clinical Phase II/III trials indicate that most RTK-targeting therapeutics including tyrosine kinase inhibitors (TKIs) and neutralizing antibodies lack clinical efficacy, either alone or in combination. The major challenge is to uncover the genetic RTK alterations driving GBM initiation and progression, as well as to elucidate the mechanisms toward therapeutic resistance. In this review, we will discuss the genetic alterations in these 5 commonly targeted RTKs, the clinical trial outcomes of the associated RTK-targeting therapeutics, and the potential mechanisms toward the resistance. We anticipate that future design of new clinical trials with combination strategies, based on the genetic alterations within an individual patient's tumor and mechanisms contributing to therapeutic resistance after treatment, will achieve durable remissions and improve outcomes in GBM patients.

Keywords:  combination therapeutics; glioblastoma; receptor tyrosine kinase; resistance mechanisms; targeted therapy

DOI:  https://doi.org/10.1093/noajnl/vdab133
Theranostics. 2021 ;11(20): 10047-10063

Therapeutic potential of parkin as a tumor suppressor via transcriptional control of cyclins in glioblastoma cell and animal models.

Lila Rouland, Eric Duplan, Lígia Ramos Dos Santos, Aurore Bernardin, Karen S Katula, Guidalberto Manfioletti, Ahmed Idbaih, Frédéric Checler, Cristine Alves da Costa.

  Parkin (PK) is an E3-ligase harboring tumor suppressor properties that has been associated to various cancer types including glioblastoma (GBM). However, PK is also a transcription factor (TF), the contribution of which to GBM etiology remains to be established. Methods: The impact of PK on GBM cells proliferation was analyzed by real-time impedance measurement and flow cytometry. Cyclins A and B proteins, promoter activities and mRNA levels were measured by western blot, luciferase assay and quantitative real-time PCR. Protein-protein and protein-promoter interactions were performed by co-immunoprecipitation and by ChIP approaches. The contribution of endogenous PK to tumor progression in vivo was performed by allografts of GL261 GBM cells in wild-type and PK knockout mice. Results: We show that overexpressed and endogenous PK control GBM cells proliferation by modulating the S and G2/M phases of the cell cycle via the trans-repression of cyclin A and cyclin B genes. We establish that cyclin B is regulated by both E3-ligase and TF PK functions while cyclin A is exclusively regulated by PK TF function. PK invalidation leads to enhanced tumor progression in immunocompetent mice suggesting an impact of PK-dependent tumor environment to tumor development. We show that PK is secreted by neuronal cells and recaptured by tumor cells. Recaptured PK lowered cyclins levels and decreased GBM cells proliferation. Further, PK expression is decreased in human GBM biopsies and its expression is inversely correlated to both cyclins A and B expressions. Conclusion: Our work demonstrates that PK tumor suppressor function contributes to the control of tumor by its cellular environment. It also shows a key role of PK TF function in GBM development via the control of cyclins in vitro and in vivo. It suggests that therapeutic strategies aimed at controlling PK shuttling to the nucleus may prove useful to treat GBM.

Keywords:  cyclins; glioblastoma; parkin; proliferation; transcription factor

DOI:  https://doi.org/10.7150/thno.57549
Nat Commun. 2021 Nov 26. 12(1): 6938

Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.

Alexander H Lee, Lu Sun, Aaron Y Mochizuki, Jeremy G Reynoso, Joey Orpilla, Frances Chow, Jenny C Kienzler, Richard G Everson, David A Nathanson, Steven J Bensinger, Linda M Liau, Timothy Cloughesy, Willy Hugo, Robert M Prins.

Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.

DOI: https://doi.org/10.1038/s41467-021-26940-2
Curr Neurol Neurosci Rep. 2021 Nov 24. 21(12): 67

The Evolving Classification of Diffuse Gliomas: World Health Organization Updates for 2021.

Alejandro Perez, Jason T Huse.

   PURPOSE OF REVIEW: The upcoming 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System will feature numerous changes in classification, diagnostic criteria, nomenclature, and grading of diffuse gliomas. This article reviews these changes and the clinical and molecular findings underlying them.
RECENT FINDINGS: Since the publication of the 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System, research has led to new insights into how molecular changes impact both the classification and grading of CNS tumors. The continued integration of molecular and histopathological features has led to changes in diagnostic criteria and grading for various tumors. In the new 2021 WHO CNS tumor classification scheme, diffuse gliomas will be classified as either adult-type diffuse gliomas, pediatric-type diffuse high-grade gliomas, or pediatric-type diffuse low-grade gliomas. The upcoming changes in the classification of adult-type and pediatric-type diffuse gliomas allow for more effective communication of both diagnostic and prognostic information, and-particularly in the case of pediatric-type diffuse gliomas-may suggest possible targeted strategies for therapeutic intervention.

Keywords:  Adult; Diffuse glioma; Genomics; Molecular; Pediatric; World Health Organization

DOI:  https://doi.org/10.1007/s11910-021-01153-8
Sci Rep. 2021 Nov 23. 11(1): 22792

The von Willebrand factor stamps plasmatic extracellular vesicles from glioblastoma patients.

Quentin Sabbagh, Gwennan André-Grégoire, Carolina Alves-Nicolau, Aurélien Dupont, Nicolas Bidère, Emmanuel Jouglar, Laëtitia Guével, Jean-Sébastien Frénel, Julie Gavard.

Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.

DOI: https://doi.org/10.1038/s41598-021-02254-7
NAR Cancer. 2021 Dec;3(4): zcab044

NAD+ bioavailability mediates PARG inhibition-induced replication arrest, intra S-phase checkpoint and apoptosis in glioma stem cells.

Jianfeng Li, Kate M Saville, Md Ibrahim, Xuemei Zeng, Steve McClellan, Anusha Angajala, Alison Beiser, Joel F Andrews, Mai Sun, Christopher A Koczor, Jennifer Clark, Faisal Hayat, Mikhail V Makarov, Anna Wilk, Nathan A Yates, Marie E Migaud, Robert W Sobol.

Elevated expression of the DNA damage response proteins PARP1 and poly(ADP-ribose) glycohydrolase (PARG) in glioma stem cells (GSCs) suggests that glioma may be a unique target for PARG inhibitors (PARGi). While PARGi-induced cell death is achieved when combined with ionizing radiation, as a single agent PARG inhibitors appear to be mostly cytostatic. Supplementation with the NAD+ precursor dihydronicotinamide riboside (NRH) rapidly increased NAD+ levels in GSCs and glioma cells, inducing PARP1 activation and mild suppression of replication fork progression. Administration of NRH+PARGi triggers hyperaccumulation of poly(ADP-ribose) (PAR), intra S-phase arrest and apoptosis in GSCs but minimal PAR induction or cytotoxicity in normal astrocytes. PAR accumulation is regulated by select PARP1- and PAR-interacting proteins. The involvement of XRCC1 highlights the base excision repair pathway in responding to replication stress while enhanced interaction of PARP1 with PCNA, RPA and ORC2 upon PAR accumulation implicates replication associated PARP1 activation and assembly with pre-replication complex proteins upon initiation of replication arrest, the intra S-phase checkpoint and the onset of apoptosis.

DOI: https://doi.org/10.1093/narcan/zcab044