bims-malgli 2022-07-03 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–07–03
eleven papers selected by
Oltea Sampetrean, Keio University

Hypoxia-induced polypoid giant cancer cells in glioma promote the transformation of tumor-associated macrophages to a tumor-supportive phenotype.
Nanomedicine for Glioblastoma: Progress and Future Prospects.
Study Sniffs Out New Glioma Mechanism.
Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation.
Rapid early progression (REP) of glioblastoma is an independent negative prognostic factor: Results from a systematic review and meta-analysis.
Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery.
Alignment between glioblastoma internal clock and environmental cues ameliorates survival in Drosophila.
Galectin-1 activates carbonic anhydrase IX and modulates glioma metabolism.
Dicer deficiency impairs proliferation but potentiates anti-tumoral effect of macrophages in glioblastoma.
Multimodal imaging of the dynamic brain tumor microenvironment during glioblastoma progression and in response to treatment.
Metabolic modeling-based drug repurposing in Glioblastoma.

CNS Neurosci Ther. 2022 Jun 28.

Hypoxia-induced polypoid giant cancer cells in glioma promote the transformation of tumor-associated macrophages to a tumor-supportive phenotype.

Yuyang Liu, Ying Shi, Mengwan Wu, Jialin Liu, Hong Wu, Chuan Xu, Ling Chen.

   AIMS: Polypoid giant cancer cells (PGCCs) represent a unique subgroup of stem-like cells, acting as a critical factor in promoting the recurrence of various solid tumors. The effect of PGCCs on the tumor malignancy of glioma and its immune microenvironment remains unclear.
METHODS: Bioinformatic analysis was performed to investigate the relationship between M2 tumor-associated macrophages (TAMs) infiltration and survival of glioblastoma (GBM) patients. The spatial location of M2 TAMs in GBM was also investigated using the Ivy Glioblastoma Atlas Project (Ivy GAP) database. PGCCs were quantified in glioma of different grades. CoCl2 was used to induce PGCCs in cultures of A172 cells. PGCCs, and their progeny cells in cultures were further evaluated for morphological features, tumorsphere formation, and TAMs activation.
RESULTS: The magnitude of M2 TAMs infiltration is significantly correlated with poor survival in GBM patients. M2 TAMs were enriched in the perinecrotic zone (PNZ) of GBM and positively correlated with hypoxic levels. Increased PGCCs were detected in glioma specimens of higher grades. CoCl2 induced hypoxia and the transformation of A172 cultures into PGCCs, producing the progeny cells, PGCCs-Dau, through asymmetric division. PGCCs and PGCCs-Dau possessed tumor stem cell-like features, while PGCCs-Dau enhanced the polarization of TAMs into an M2 phenotype with relevance to immunosuppression and malignancy in GBM.
CONCLUSIONS: PGCCs promote malignancy and immune-suppressive microenvironment in GBM. PGCCs or their progeny cells may be a potential therapeutic target for GBM.

Keywords:  glioma; hypoxia; polypoid giant cancer cell; tumor-associated macrophages

DOI:  https://doi.org/10.1111/cns.13892
Semin Cancer Biol. 2022 Jun 24. pii: S1044-579X(22)00141-9. [Epub ahead of print]

Nanomedicine for Glioblastoma: Progress and Future Prospects.

Imran Khan, Mohammad Hassan Baig, Sadaf Mahfooz, Mohammad Azhar Imran, Mohd Imran Khan, Jae-June Dong, Jae Yong Cho, Mustafa Aziz Hatiboglu.

  Glioblastoma is the most aggressive form of brain tumor, accounting for the highest mortality and morbidity rates. Current treatment for patients with glioblastoma includes maximal safe tumor resection followed by radiation therapy with concomitant temozolomide (TMZ) chemotherapy. The addition of TMZ to the conformal radiation therapy has improved the median survival time only from 12 months to 16 months in patients with glioblastoma. Despite these aggressive treatment strategies, patients' prognosis remains poor. This therapeutic failure is primarily attributed to the blood-brain barrier (BBB) that restricts the transport of TMZ from reaching the tumor site. In recent years, nanomedicine has gained considerable attention among researchers and shown promising developments in clinical applications, including the diagnosis, prognosis, and treatment of glioblastoma tumors. This review sheds light on the morphological and physiological complexity of the BBB. It also explains the development of nanomedicine strategies to enhance the permeability of drug molecules across the BBB.

Keywords:  Nanoparticle; blood brain barrier; exosomes; glioblastoma; liposomes

DOI:  https://doi.org/10.1016/j.semcancer.2022.06.007
Cancer Discov. 2022 Jun 30. OF1

Study Sniffs Out New Glioma Mechanism.

A recent study showed that olfaction may play a role in the development of gliomas in cancer-prone mice. Researchers found that stimulating olfactory neurons promotes tumor growth in the animals, whereas inhibiting the neurons leads to smaller gliomas. The study also determined that mice with one plugged nostril had larger tumors on the unobstructed side.

DOI: https://doi.org/10.1158/2159-8290.CD-NB2022-0048
Cell Death Dis. 2022 Jun 28. 13(6): 573

Liver glycogen phosphorylase is upregulated in glioblastoma and provides a metabolic vulnerability to high dose radiation.

Christos E Zois, Anne M Hendriks, Syed Haider, Elisabete Pires, Esther Bridges, Dimitra Kalamida, Dimitrios Voukantsis, B Christoffer Lagerholm, Rudolf S N Fehrmann, Wilfred F A den Dunnen, Andrei I Tarasov, Otto Baba, John Morris, Francesca M Buffa, James S O McCullagh, Mathilde Jalving, Adrian L Harris.

Channelling of glucose via glycogen, known as the glycogen shunt, may play an important role in the metabolism of brain tumours, especially in hypoxic conditions. We aimed to dissect the role of glycogen degradation in glioblastoma (GBM) response to ionising radiation (IR). Knockdown of the glycogen phosphorylase liver isoform (PYGL), but not the brain isoform (PYGB), decreased clonogenic growth and survival of GBM cell lines and sensitised them to IR doses of 10-12 Gy. Two to five days after IR exposure of PYGL knockdown GBM cells, mitotic catastrophy and a giant multinucleated cell morphology with senescence-like phenotype developed. The basal levels of the lysosomal enzyme alpha-acid glucosidase (GAA), essential for autolysosomal glycogen degradation, and the lipidated forms of gamma-aminobutyric acid receptor-associated protein-like (GABARAPL1 and GABARAPL2) increased in shPYGL U87MG cells, suggesting a compensatory mechanism of glycogen degradation. In response to IR, dysregulation of autophagy was shown by accumulation of the p62 and the lipidated form of GABARAPL1 and GABARAPL2 in shPYGL U87MG cells. IR increased the mitochondrial mass and the colocalisation of mitochondria with lysosomes in shPYGL cells, thereby indicating reduced mitophagy. These changes coincided with increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase 2, slower ATP generation in response to glucose loading and progressive loss of oxidative phosphorylation. The resulting metabolic deficiencies affected the availability of ATP required for mitosis, resulting in the mitotic catastrophy observed in shPYGL cells following IR. PYGL mRNA and protein levels were higher in human GBM than in normal human brain tissues and high PYGL mRNA expression in GBM correlated with poor patient survival. In conclusion, we show a major new role for glycogen metabolism in GBM cancer. Inhibition of glycogen degradation sensitises GBM cells to high-dose IR indicating that PYGL is a potential novel target for the treatment of GBMs.

DOI: https://doi.org/10.1038/s41419-022-05005-2
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac075

Rapid early progression (REP) of glioblastoma is an independent negative prognostic factor: Results from a systematic review and meta-analysis.

Mueez Waqar, Federico Roncaroli, Eric J Lehrer, Joshua D Palmer, Javier Villanueva-Meyer, Steve Braunstein, Emma Hall, Marianne Aznar, Philip C De Witt Hamer, Pietro I D'Urso, Daniel Trifiletti, Alfredo Quiñones-Hinojosa, Pieter Wesseling, Gerben R Bors.

   Background: In patients with newly diagnosed glioblastoma, rapid early progression (REP) refers to tumor regrowth between surgery and postoperative chemoradiotherapy. This systematic review and meta-analysis appraised previously published data on REP to better characterize and understand it.
Methods: Systematic searches of MEDLINE, EMBASE and the Cochrane database from inception to October 21, 2021. Studies describing the incidence of REP-tumor growth between the postoperative MRI scan and pre-radiotherapy MRI scan in newly diagnosed glioblastoma were included. The primary outcome was REP incidence.
Results: From 1590 search results, 9 studies were included with 716 patients. The median age was 56.9 years (IQR 54.0-58.8 y). There was a male predominance with a median male-to-female ratio of 1.4 (IQR 1.1-1.5). The median number of days between MRI scans was 34 days (IQR 18-45 days). The mean incidence rate of REP was 45.9% (range 19.3%-72.0%) and significantly lower in studies employing functional imaging to define REP (P < .001). REP/non-REP groups were comparable with respect to age (P = .99), gender (P = .33) and time between scans (P = .81). REP was associated with shortened overall survival (HR 1.78, 95% CI 1.30-2.43, P < .001), shortened progression-free survival (HR 1.78, 95% CI 1.30-2.43, P < .001), subtotal resection (OR 6.96, 95% CI 4.51-10.73, P < .001) and IDH wild-type versus mutant tumors (OR 0.20, 95% CI 0.02-0.38, P = .03). MGMT promoter methylation was not associated with REP (OR 1.29, 95% CI 0.72-2.28, P = .39).
Conclusions: REP occurs in almost half of patients with newly diagnosed glioblastoma and has a strongly negative prognostic effect. Future studies should investigate its biology and effective treatment strategies.

Keywords:  IDH; MGMT; REP; extent of resection; glioblastoma; prognosis; progression; recurrence; survival

DOI:  https://doi.org/10.1093/noajnl/vdac075
Sci Adv. 2022 Jul;8(26): eabn9440

Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery.

Tala Shekarian, Carl P Zinner, Ewelina M Bartoszek, Wandrille Duchemin, Anna T Wachnowicz, Sabrina Hogan, Manina M Etter, Julia Flammer, Chiara Paganetti, Tomas A Martins, Philip Schmassmann, Steven Zanganeh, Francois Le Goff, Manuele G Muraro, Marie-Françoise Ritz, Darci Phillips, Salil S Bhate, Graham L Barlow, Garry P Nolan, Christian M Schürch, Gregor Hutter.

A patient-tailored, ex vivo drug response platform for glioblastoma (GBM) would facilitate therapy planning, provide insights into treatment-induced mechanisms in the immune tumor microenvironment (iTME), and enable the discovery of biomarkers of response. We cultured regionally annotated GBM explants in perfusion bioreactors to assess iTME responses to immunotherapy. Explants were treated with anti-CD47, anti-PD-1, or their combination, and analyzed by multiplexed microscopy [CO-Detection by indEXing (CODEX)], enabling the spatially resolved identification of >850,000 single cells, accompanied by explant secretome interrogation. Center and periphery explants differed in their cell type and soluble factor composition, and responses to immunotherapy. A subset of explants displayed increased interferon-γ levels, which correlated with shifts in immune cell composition within specified tissue compartments. Our study demonstrates that ex vivo immunotherapy of GBM explants enables an active antitumoral immune response within the tumor center and provides a framework for multidimensional personalized assessment of tumor response to immunotherapy.

DOI: https://doi.org/10.1126/sciadv.abn9440
Commun Biol. 2022 Jun 30. 5(1): 644

Alignment between glioblastoma internal clock and environmental cues ameliorates survival in Drosophila.

Patricia Jarabo, Celia G Barredo, Carmen de Pablo, Sergio Casas-Tinto, Francisco A Martin.

Virtually every single living organism on Earth shows a circadian (i.e. "approximately a day") internal rhythm that is coordinated with planet rotation (i.e. 24 hours). External cues synchronize the central clock of the organism. Consequences of biological rhythm disruptions have been extensively studied on cancer. Still, mechanisms underlying these alterations, and how they favor tumor development remain largely unknown. Here, we show that glioblastoma-induced neurodegeneration also causes circadian alterations in Drosophila. Preventing neurodegeneration in all neurons by genetic means reestablishes normal biological rhythms. Interestingly, in early stages of tumor development, the central pacemaker lengthens its period, whereas in later stages this is severely disrupted. The re-adjustment of the external light:dark period to longer glioblastoma-induced internal rhythms delays glioblastoma progression and ameliorates associated deleterious effects, even after the tumor onset.

DOI: https://doi.org/10.1038/s42003-022-03600-9
Cell Death Dis. 2022 Jun 30. 13(6): 574

Galectin-1 activates carbonic anhydrase IX and modulates glioma metabolism.

Maheedhara R Guda, Andrew J Tsung, Swapna Asuthkar, Kiran K Velpula.

Galectins are a family of β-galactose-specific binding proteins residing within the cytosol or nucleus, with a highly conserved carbohydrate recognition domain across many species. Accumulating evidence shows that Galectin 1 (Gal-1) plays an essential role in cancer, and its expression correlates with tumor aggressiveness and progression. Our preliminary data showed Gal-1 promotes glioma stem cell (GSC) growth via increased Warburg effect. mRNA expression and clinical data were obtained from The Cancer Genome Atlas database. The immunoblot analysis conducted using our cohort of human glioblastoma patient specimens (hGBM), confirmed Gal-1 upregulation in GBM. GC/MS analysis to evaluate the effects of Gal-1 depletion showed elevated levels of α-ketoglutaric acid, and citric acid with a concomitant reduction in lactic acid levels. Using Biolog microplate-1 mitochondrial functional assay, we confirmed that the depletion of Gal-1 increases the expression levels of the enzymes from the TCA cycle, suggesting a reversal of the Warburg phenotype. Manipulation of Gal-1 using RNA interference showed reduced ATP, lactate levels, cell viability, colony-forming abilities, and increased expression levels of genes implicated in the induction of apoptosis. Gal-1 exerts its metabolic role via regulating the expression of carbonic anhydrase IX (CA-IX), a surrogate marker for hypoxia. CA-IX functions downstream to Gal-1, and co-immunoprecipitation experiments along with proximity ligation assays confirm that Gal-1 physically associates with CA-IX to regulate its expression. Further, silencing of Gal-1 in mice models showed reduced tumor burden and increased survival compared to the mice implanted with GSC controls. Further investigation of Gal-1 in GSC progression and metabolic reprogramming is warranted.

DOI: https://doi.org/10.1038/s41419-022-05024-z
Oncogene. 2022 Jun 28.

Dicer deficiency impairs proliferation but potentiates anti-tumoral effect of macrophages in glioblastoma.

Yu-Qi Liu, Min Luo, Yu Shi, Ying Guo, Hua Zhang, Kai-Di Yang, Tian-Ran Li, Liu-Qing Yang, Ting-Ting Liu, Bo Huang, Qing Liu, Zhi-Cheng He, Xiao-Ning Zhang, Wen-Ying Wang, Shuai Wang, Hui Zeng, Qin Niu, Xia Zhang, You-Hong Cui, Zhi-Ren Zhang, Xiu-Wu Bian, Yi-Fang Ping.

Glioblastoma is a lethal primary brain tumor with abundant immune-suppressive glioblastoma-associated macrophage (GAM) infiltration. Skewing immune suppressive GAMs towards an immune-activating phenotype represents a promising immunotherapeutic strategy against glioblastoma. Herein, we reported that genetic deletion of miRNA-processing enzyme Dicer in macrophages inhibited the growth of GL261 murine glioblastoma xenografts and prolonged survival of tumor-bearing mice. Single cell RNA sequencing (scRNA-seq) of the tumor-infiltrating immune cells revealed that Dicer deletion in macrophages reduced the proportion of cell-cycling GAM cluster and reprogramed the remaining GAMs towards a proinflammatory activation state (enhanced phagocytotic and IFN-producing signature). Dicer-deficient GAMs showed reduced level of cyclin-dependent kinases (CDK1 and CDK2) and increased expression of CDK inhibitor p27 Kip1, thus manifesting impaired proliferation. Dicer knockout enhanced phagocytotic activity of GAMs to eliminate GL261 tumor cells. Increased proinflammatory GAM clusters in macrophage Dicer-deficient mice actively interacted with tumor-infiltrating T cells and NK cells through TNF paracrine signaling to create a pro-inflammatory immune microenvironment for tumor cell elimination. Our work identifies the role of Dicer deletion in macrophages in generating an immune-activating microenvironment, which could be further developed as a potential immunotherapeutic strategy against glioblastoma.

DOI: https://doi.org/10.1038/s41388-022-02393-9
iScience. 2022 Jul 15. 25(7): 104570

Multimodal imaging of the dynamic brain tumor microenvironment during glioblastoma progression and in response to treatment.

Anoek Zomer, Davide Croci, Joanna Kowal, Leon van Gurp, Johanna A Joyce.

  Tumors evolve in a dynamic communication with their native tissue environment and recruited immune cells. The diverse components of the tumor microenvironment (TME) can critically regulate tumor progression and therapeutic response. In turn, anticancer treatments may alter the composition and functions of the TME. To investigate this continuous dialog in the context of primary brain cancers, we developed a multimodal longitudinal imaging strategy. We combined macroscopical magnetic resonance imaging with subcellular resolution two-photon intravital microscopy, and leveraged the power of single-cell analysis tools to gain insights into the ongoing interactions between different components of the TME and cancer cells. Our experiments revealed that the migratory behavior of tumor-associated macrophages is different in genetically distinct glioblastomas, and in response to macrophage-targeted therapy. These results underscore the importance of studying cancer longitudinally in an in vivo setting, to reveal complex and dynamic alterations in the TME during disease progression and therapeutic intervention.

Keywords:  Cancer; Medical imaging; Microenvironment; Physics magnetic resonance imaging

DOI:  https://doi.org/10.1016/j.isci.2022.104570
Sci Rep. 2022 Jul 01. 12(1): 11189

Metabolic modeling-based drug repurposing in Glioblastoma.

Claudio Tomi-Andrino, Alina Pandele, Klaus Winzer, John King, Ruman Rahman, Dong-Hyun Kim.

The manifestation of intra- and inter-tumor heterogeneity hinders the development of ubiquitous cancer treatments, thus requiring a tailored therapy for each cancer type. Specifically, the reprogramming of cellular metabolism has been identified as a source of potential drug targets. Drug discovery is a long and resource-demanding process aiming at identifying and testing compounds early in the drug development pipeline. While drug repurposing efforts (i.e., inspecting readily available approved drugs) can be supported by a mechanistic rationale, strategies to further reduce and prioritize the list of potential candidates are still needed to facilitate feasible studies. Although a variety of 'omics' data are widely gathered, a standard integration method with modeling approaches is lacking. For instance, flux balance analysis is a metabolic modeling technique that mainly relies on the stoichiometry of the metabolic network. However, exploring the network's topology typically neglects biologically relevant information. Here we introduce Transcriptomics-Informed Stoichiometric Modelling And Network analysis (TISMAN) in a recombinant innovation manner, allowing identification and validation of genes as targets for drug repurposing using glioblastoma as an exemplar.

DOI: https://doi.org/10.1038/s41598-022-14721-w