bims-malgli 2020-06-21 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2020–06–21
twelve papers selected by
Oltea Sampetrean, Keio University

Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma.
Radiosensitizers in the temozolomide era for newly diagnosed glioblastoma.
Anti-PD-1 induces M1 polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 cytotoxic T cells.
Glioblastomas located in proximity to the subventricular zone (SVZ) exhibited enrichment of gene expression profiles associated with the cancer stem cell state.
Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.
Selective, high-contrast detection of syngeneic glioblastoma in vivo.
GlioM&M: Web-based tool for studying circulating and infiltrating monocytes and macrophages in glioma.
Apelin Controls Angiogenesis-Dependent Glioblastoma Growth.
Cross talk between mesenchymal and glioblastoma stem cells: Communication beyond controversies.
The integrated genomic and epigenomic landscape of brainstem glioma.
On-Site Sampling and Extraction of Brain Tumors for Metabolomics and Lipidomics Analysis.
Molecular-Targeted Therapy for Childhood Brain Tumors: A Moving Target.

Nat Commun. 2020 Jun 15. 11(1): 3015

Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma.

Weiwei Tao, Chengwei Chu, Wenchao Zhou, Zhi Huang, Kui Zhai, Xiaoguang Fang, Qian Huang, Aili Zhang, Xiuxing Wang, Xingjiang Yu, Haidong Huang, Qiulian Wu, Andrew E Sloan, Jennifer S Yu, Xiaoxia Li, George R Stark, Jeremy N Rich, Shideng Bao.

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6β1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/β-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/β-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.

DOI: https://doi.org/10.1038/s41467-020-16827-z
Neurooncol Pract. 2020 Jun;7(3): 268-276

Radiosensitizers in the temozolomide era for newly diagnosed glioblastoma.

Peter Mathen, Lindsay Rowe, Megan Mackey, DeeDee Smart, Philip Tofilon, Kevin Camphausen.

  Glioblastoma (GBM) is a challenging diagnosis with almost universally poor prognosis. Though the survival advantage of postoperative radiation (RT) is well established, around 90% of patients will fail in the RT field. The high likelihood of local failure suggests the efficacy of RT needs to be improved to improve clinical outcomes. Radiosensitizers are an established method of enhancing RT cell killing through the addition of a pharmaceutical agent. Though the majority of trials using radiosensitizers have historically been unsuccessful, there continues to be interest with a variety of approaches having been employed. Epidermal growth factor receptor inhibitors, histone deacetylase inhibitors, antiangiogenic agents, and a number of other molecularly targeted agents have all been investigated as potential methods of radiosensitization in the temozolomide era. Outcomes have varied both in terms of toxicity and survival, but some agents such as valproic acid and bortezomib have demonstrated promising results. However, reporting of results in phase 2 trials in newly diagnosed GBM have been inconsistent, with no standard in reporting progression-free survival and toxicity. There is a pressing need for investigation of new agents; however, nearly all phase 3 trials of GBM patients of the past 25 years have demonstrated no improvement in outcomes. One proposed explanation for this is the selection of agents lacking sufficient preclinical data and/or based on poorly designed phase 2 trials. Radiosensitization may represent a viable strategy for improving GBM outcomes in newly diagnosed patients, and further investigation using agents with promising phase 2 data is warranted.

Keywords:  glioblastoma; glioma; newly diagnosed; radiosensitizer; temozolomide

DOI:  https://doi.org/10.1093/nop/npz057
Clin Cancer Res. 2020 Jun 18. pii: clincanres.4110.2019. [Epub ahead of print]

Anti-PD-1 induces M1 polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 cytotoxic T cells.

Ganesh Rao, Khatri Latha, Martina Ott, Aria Sabbagh, Anantha Marisetty, Xiaoyang Ling, Daniel B Zamler, Tiffany Doucette, Yuhui Yang, Ling-Yuan Kong, Jun Wei, Gregory N Fuller, Fernando Benavides, Adam M Sonabend, James P Long, Shulin Li, Michael A Curran, Amy B Heimberger.

PURPOSE: Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated inconsistent therapeutic results in patients with glioblastoma (GBM) including those with profound impairments in CD8 T cell effector responses Experimental Design: . We observed a survival benefit in immunocompetent mice with endogenously-arising intracranial glioblastomas after intravenous administration of anti-PD-1. The therapeutic effect of PD-1 administration persisted in mice even after genetic ablation of the CD8 gene (CD8-/-). CD11b+ and Iba1+ monocytes and macrophages were enriched in the glioma microenvironment of the CD8-/- mice Results: The macrophages and microglia assumed a proinflammatory M1 response signature in the setting of anti-PD-1 blockade through the elimination of PD-1-expressing macrophages and microglia in the tumor microenvironment. Anti-PD-1 can inhibit the proliferation of and induce apoptosis of microglia through Ab-dependent cellular cytotoxicity (ADCC), as fluorescently-labeled anti-PD-1 was shown to gain direct access to the glioma microenvironment.
CONCLUSIONS: Our results show that the therapeutic effect of anti-PD-1 blockade in GBM may be mediated by the innate immune system, rather than by CD8 T cells.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-4110
J Neurooncol. 2020 Jun 15.

Glioblastomas located in proximity to the subventricular zone (SVZ) exhibited enrichment of gene expression profiles associated with the cancer stem cell state.

Tyler C Steed, Jeffrey M Treiber, Birra Taha, H Billur Engin, Hannah Carter, Kunal S Patel, Anders M Dale, Bob S Carter, Clark C Chen.

INTRODUCTION: Conflicting results have been reported in the association between glioblastoma proximity to the subventricular zone (SVZ) and enrichment of cancer stem cell properties. Here, we examined this hypothesis using magnetic resonance (MR) images derived from 217 The Cancer Imaging Archive (TCIA) glioblastoma subjects.
METHODS: Pre-operative MR images were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Distances were calculated from the centroid of CE tumor volumes to the SVZ and correlated with gene expression profiles of the corresponding glioblastomas. Correlative analyses were performed between SVZ distance, gene expression patterns, and clinical survival.
RESULTS: Glioblastoma located in proximity to the SVZ showed increased mRNA expression patterns associated with the cancer stem-cell state, including CD133 (P = 0.006). Consistent with the previous observations suggesting that glioblastoma stem cells exhibit increased DNA repair capacity, glioblastomas in proximity to the SVZ also showed increased expression of DNA repair genes, including MGMT (P = 0.018). Reflecting this enhanced DNA repair capacity, the genomes of glioblastomas in SVZ proximity harbored fewer single nucleotide polymorphisms relative to those located distant to the SVZ (P = 0.003). Concordant with the notion that glioblastoma stem cells are more aggressive and refractory to therapy, patients with glioblastoma in proximity to SVZ exhibited poorer progression free and overall survival (P < 0.01).
CONCLUSION: An unbiased analysis of TCIA suggests that glioblastomas located in proximity to the SVZ exhibited mRNA expression profiles associated with stem cell properties, increased DNA repair capacity, and is associated with poor clinical survival.

DOI: https://doi.org/10.1007/s11060-020-03550-4
Cell Metab. 2020 Jun 09. pii: S1550-4131(20)30303-X. [Epub ahead of print]

Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

Xiang Cheng, Feng Geng, Meixia Pan, Xiaoning Wu, Yaogang Zhong, Chunyan Wang, Zhihua Tian, Chunming Cheng, Rui Zhang, Vinay Puduvalli, Craig Horbinski, Xiaokui Mo, Xianlin Han, Arnab Chakravarti, Deliang Guo.

  Glioblastoma (GBM), a mostly lethal brain tumor, acquires large amounts of free fatty acids (FAs) to promote cell growth. But how the cancer avoids lipotoxicity is unknown. Here, we identify that GBM upregulates diacylglycerol-acyltransferase 1 (DGAT1) to store excess FAs into triglycerides and lipid droplets. Inhibiting DGAT1 disrupted lipid homeostasis and resulted in excessive FAs moving into mitochondria for oxidation, leading to the generation of high levels of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release, and apoptosis. Adding N-acetyl-cysteine or inhibiting FA shuttling into mitochondria decreased ROS and cell death induced by DGAT1 inhibition. We show in xenograft models that targeting DGAT1 blocked lipid droplet formation, induced tumor cell apoptosis, and markedly suppressed GBM growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating storage of excess FAs. Targeting DGAT1 could be a promising therapeutic approach for GBM.

Keywords:  DGAT1; ROS; acylcarnitine; fatty acids; glioblastoma; lipid droplets; lipotoxicity; mitochondria; oxidative stress; triglycerides

DOI:  https://doi.org/10.1016/j.cmet.2020.06.002
Sci Rep. 2020 Jun 19. 10(1): 9968

Selective, high-contrast detection of syngeneic glioblastoma in vivo.

Richard B Banati, Paul Wilcox, Ran Xu, Grace Yin, Emily Si, Eric Taeyoung Son, Mauricio Shimizu, R M Damian Holsinger, Arvind Parmar, David Zahra, Andrew Arthur, Ryan J Middleton, Guo-Jun Liu, Arnaud Charil, Manuel B Graeber.

Glioblastoma is a highly malignant, largely therapy-resistant brain tumour. Deep infiltration of brain tissue by neoplastic cells represents the key problem of diffuse glioma. Much current research focuses on the molecular makeup of the visible tumour mass rather than the cellular interactions in the surrounding brain tissue infiltrated by the invasive glioma cells that cause the tumour's ultimately lethal outcome. Diagnostic neuroimaging that enables the direct in vivo observation of the tumour infiltration zone and the local host tissue responses at a preclinical stage are important for the development of more effective glioma treatments. Here, we report an animal model that allows high-contrast imaging of wild-type glioma cells by positron emission tomography (PET) using [18 F]PBR111, a selective radioligand for the mitochondrial 18 kDa Translocator Protein (TSPO), in the Tspo-/- mouse strain (C57BL/6-Tspotm1GuMu(GuwiyangWurra)). The high selectivity of [18 F]PBR111 for the TSPO combined with the exclusive expression of TSPO in glioma cells infiltrating into null-background host tissue free of any TSPO expression, makes it possible, for the first time, to unequivocally and with uniquely high biological contrast identify peri-tumoral glioma cell invasion at preclinical stages in vivo. Comparison of the in vivo imaging signal from wild-type glioma cells in a null background with the signal in a wild-type host tissue, where the tumour induces the expected TSPO expression in the host's glial cells, illustrates the substantial extent of the peritumoral host response to the growing tumour. The syngeneic tumour (TSPO+/+) in null background (TSPO-/-) model is thus well suited to study the interaction of the tumour front with the peri-tumoral tissue, and the experimental evaluation of new therapeutic approaches targeting the invasive behaviour of glioblastoma.

DOI: https://doi.org/10.1038/s41598-020-67036-z
Sci Rep. 2020 Jun 18. 10(1): 9898

GlioM&M: Web-based tool for studying circulating and infiltrating monocytes and macrophages in glioma.

Erik R Abels, Sybren L N Maas, Eric Tai, David T Ting, Marike L D Broekman, Xandra O Breakefield, Joseph El Khoury.

Monocytes, macrophages and microglia make up a large part of the glioma environment and have an important role in maintaining and propagating glioma progression. Targeting these cells to inhibit their tumor-promoting effect and reprogramming them into an anti-tumor phenotype is a potential therapeutic approach for glioma. In this study we analyzed the transcriptomes of eight different monocyte subgroups derived from the brain and the blood of glioma-bearing mice. We compared the expression profile of blood-derived monocytes versus tumor-infiltrating monocytes and found increased expression of both pro- and anti-inflammatory pathways in tumor infiltrating monocytes. To help disseminate these datasets, we created a user-friendly web-based tool accessible at www.glioma-monocytes.com. This tool can be used for validation purposes and to elucidate gene expression profiles of tumor-interacting monocytes and macrophages as well as blood-derived circulating monocytes. This tool can also be used to identify new markers and targets for therapy in these different cell populations.

DOI: https://doi.org/10.1038/s41598-020-66728-w
Int J Mol Sci. 2020 Jun 11. pii: E4179. [Epub ahead of print]21(11):

Apelin Controls Angiogenesis-Dependent Glioblastoma Growth.

Anne Frisch, Stefanie Kälin, Raymond Monk, Josefine Radke, Frank L Heppner, Roland E Kälin.

  Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor (APLNR) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived APLN massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the APLN-knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, APLN depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when APLN expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM.

Keywords:  APLN; APLNR; Apelin-13; GBM angiogenesis; glioblastoma

DOI:  https://doi.org/10.3390/ijms21114179
Stem Cells Transl Med. 2020 Jun 15.

Cross talk between mesenchymal and glioblastoma stem cells: Communication beyond controversies.

Adriana Bajetto, Stefano Thellung, Irene Dellacasagrande, Aldo Pagano, Federica Barbieri, Tullio Florio.

  Mesenchymal stem cells (MSCs) can be isolated from bone marrow or other adult tissues (adipose tissue, dental pulp, amniotic fluid, and umbilical cord). In vitro, MSCs grow as adherent cells, display fibroblast-like morphology, and self-renew, undergoing specific mesodermal differentiation. High heterogeneity of MSCs from different origin, and differences in preparation techniques, make difficult to uniform their functional properties for therapeutic purposes. Immunomodulatory, migratory, and differentiation ability, fueled clinical MSC application in regenerative medicine, whereas beneficial effects are currently mainly ascribed to their secretome and extracellular vesicles. MSC translational potential in cancer therapy exploits putative anti-tumor activity and inherent tropism toward tumor sites to deliver cytotoxic drugs. However, controversial results emerged evaluating either the therapeutic potential or homing efficiency of MSCs, as both antitumor and protumor effects were reported. Glioblastoma (GBM) is the most malignant brain tumor and its development and aggressive nature is sustained by cancer stem cells (CSCs) and the identification of effective therapeutic is required. MSC dualistic action, tumor-promoting or tumor-targeting, is dependent on secreted factors and extracellular vesicles driving a complex cross talk between MSCs and GBM CSCs. Tumor-tropic ability of MSCs, besides providing an alternative therapeutic approach, could represent a tool to understand the biology of GBM CSCs and related paracrine mechanisms, underpinning MSC-GBM interactions. In this review, recent findings on the complex nature of MSCs will be highlighted, focusing on their elusive impact on GBM progression and aggressiveness by direct cell-cell interaction and via secretome, also facing the perspectives and challenges in treatment strategies.

Keywords:  cancer stem cells; extracellular vesicles; glioblastoma; mesenchymal stem cells; secretoma

DOI:  https://doi.org/10.1002/sctm.20-0161
Nat Commun. 2020 Jun 17. 11(1): 3077

The integrated genomic and epigenomic landscape of brainstem glioma.

Lee H Chen, Changcun Pan, Bill H Diplas, Cheng Xu, Landon J Hansen, Yuliang Wu, Xin Chen, Yibo Geng, Tao Sun, Yu Sun, Peng Zhang, Zhen Wu, Junting Zhang, Deling Li, Yang Zhang, Wenhao Wu, Yu Wang, Guangyu Li, Jie Yang, Xiaoyue Wang, Ce Xu, Sizhen Wang, Matthew S Waitkus, Yiping He, Roger E McLendon, David M Ashley, Hai Yan, Liwei Zhang.

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.

DOI: https://doi.org/10.1038/s41467-020-16682-y
J Vis Exp. 2020 May 31.

On-Site Sampling and Extraction of Brain Tumors for Metabolomics and Lipidomics Analysis.

Joanna Bogusiewicz, Paulina Zofia Goryńska, Magdalena Gaca, Kamila Chmara, Krzysztof Goryński, Karol Jaroch, Dariusz Paczkowski, Jacek Furtak, Marek Harat, Barbara Bojko.

Despite the variety of tools available for cancer diagnosis and classification, methods that enable fast and simple characterization of tumors are still in need. In recent years, mass spectrometry has become a method of choice for untargeted profiling of discriminatory compound as potential biomarkers of a disease. Biofluids are generally considered as preferable matrices given their accessibility and easier sample processing while direct tissue profiling provides more selective information about a given cancer. Preparation of tissues for the analysis via traditional methods is much more complex and time-consuming, and, therefore, not suitable for fast on-site analysis. The current work presents a protocol combining sample preparation and extraction of small molecules on-site, immediately after tumor resection. The sampling device, which is of the size of an acupuncture needle, can be inserted directly into the tissue and then transported to the nearby laboratory for instrumental analysis. The results of metabolomics and lipidomics analyses demonstrate the capability of the approach for the establishment of phenotypes of tumors related to the histological origin of the tumor, malignancy, and genetic mutations, as well as for the selection of discriminating compounds or potential biomarkers. The non-destructive nature of the technique permits subsequent performance of routinely used tests e.g., histological tests, on the same samples used for SPME analysis, thus enabling attainment of more comprehensive information to support personalized diagnostics.

DOI: https://doi.org/10.3791/61260
J Child Neurol. 2020 Jun 18. 883073820931635

Molecular-Targeted Therapy for Childhood Brain Tumors: A Moving Target.

Roger J Packer, Lindsay Kilburn.

  Molecular-targeted therapy is an attractive therapeutic approach for childhood brain tumors. Unfortunately, with some notable exceptions, such treatment has not yet made a major impact on survival or for that matter quality-of-life for children with brain tumors. Limitations include the specificity of any single agent to inhibit the target, the presence of multiple genetic abnormalities within a tumor, the likely presence of escape mechanisms and the frequent use of molecular-targeted therapies in relatively biologically unselected patient populations. Despite these limitations, the MEK inhibitors and the BRAF V600E inhibitors have already demonstrated efficacy and are being compared to standard therapy in trials of treatment-naïve patients. There is also great enthusiasm for molecular-targeted therapies that target selective gene fusions. Given the plasticity of epigenetic changes, the targeting of epigenetic aberrations is also a promising avenue of therapy. Because molecular-targeted therapies frequently target genes and pathways that are critical in normal brain development, the acute, subacute long-term sequelae of molecular-targeted therapies need to be carefully monitored.

Keywords:  BRAF; MEK inhibitors; childhood brain tumors; molecularly targeted therapy; tyrosine kinase inhibitors

DOI:  https://doi.org/10.1177/0883073820931635