Oncometabolite R-2 hydroxyglutarate aids the inflammatory transformation of peritumoral astrocytes

Abstract Reactive transformation of astrocytes in IDH wild-type glioma contribute to anti-tumor immunity and support pro-oncogenic signaling. The role of intra- and peritumoral astrocytes in IDH1/2 mutated glioma, a prognostically beneficial subgroup with oncogene-driven enrichment of R-2-hydroxygluterate (2-HG) remains sparsely explored. Here, we characterized the transcriptomic signature of IDH1/2-mutant glioma associated astrocytes and determined a unique inflammatory transformation, profoundly different to astrocytes in IDH wildtype glioma patients. IDH-mutated glioma inoculation into human neocortical sections or treatment with R-2-HG resulted in an oncometabolite-mediated transcriptional shift towards inflammation in astrocytes. This transcriptional shift was found to be mediated by myeloid cell polarization through R-2-HG in the tumor microenvironment, which was further confirmed by selective depletion of myeloid cells. Integrative analysis of bulk RNA-sequencing of purified microglia, single-cell transcriptomics and spatially resolved transcriptomics confirmed this microglia-mediated inflammatory activation of astrocytes. This inflammatory activation is accompanied by loss of neurotransmitter homeostasis. Further, treatment of cortical sections with RH2G results in increased neuronal activity and LFP activity, pointing to the excitotoxic nature of RH2G in the neural microenvironment, with a significant loss of neurons with chronic treatment. The presented findings provide insights into the role that R-2HG plays in the reactive transformation of astrocytes within the IDH-mutated tumor environment and is fundamentally different that seen in IDH wildtype glioma.

Download Full-text

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer

Pharmaceuticals ◽

10.3390/ph13100292 ◽

2020 ◽

Vol 13 (10) ◽

pp. 292

Author(s):

Barbara Guerra ◽

Olaf-Georg Issinger

Keyword(s):

Lipid Metabolism ◽

Protein Kinase ◽

Cancer Cells ◽

Intracellular Signaling ◽

Metabolic Reprogramming ◽

Oncogenic Signaling ◽

Combination Strategies ◽

Tumor Environment ◽

Kinase Ck2

Uncontrolled proliferation is a feature defining cancer and it is linked to the ability of cancer cells to effectively adapt their metabolic needs in response to a harsh tumor environment. Metabolic reprogramming is considered a hallmark of cancer and includes increased glucose uptake and processing, and increased glutamine utilization, but also the deregulation of lipid and cholesterol-associated signal transduction, as highlighted in recent years. In the first part of the review, we will (i) provide an overview of the major types of lipids found in eukaryotic cells and their importance as mediators of intracellular signaling pathways (ii) analyze the main metabolic changes occurring in cancer development and the role of oncogenic signaling in supporting aberrant lipid metabolism and (iii) discuss combination strategies as powerful new approaches to cancer treatment. The second part of the review will address the emerging role of CK2, a conserved serine/threonine protein kinase, in lipid homeostasis with an emphasis regarding its function in lipogenesis and adipogenesis. Evidence will be provided that CK2 regulates these processes at multiple levels. This suggests that its pharmacological inhibition combined with dietary restrictions and/or inhibitors of metabolic targets could represent an effective way to undermine the dependency of cancer cells on lipids to interfere with tumor progression.

Download Full-text

The photoreceptor cytoskeleton visualized

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100122800 ◽

1992 ◽

Vol 50 (1) ◽

pp. 480-481

Author(s):

Beth Burnside

Keyword(s):

Outer Segment ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Cell Polarization ◽

Synaptic Proteins ◽

Cell Functions ◽

Vertebrate Photoreceptor ◽

Numerous Cell ◽

Turn Over

The vertebrate photoreceptor provides a drammatic example of cell polarization. Specialized to carry out phototransduction at its distal end and to synapse with retinal interneurons at its proximal end, this long slender cell has a uniquely polarized morphology which is reflected in a similarly polarized cytoskeleton. Membranes bearing photopigment are localized in the outer segment, a modified sensory cilium. Sodium pumps which maintain the dark current critical to photosensory transduction are anchored along the inner segment plasma membrane between the outer segment and the nucleus.Proximal to the nucleus is a slender axon terminating in specialized invaginating synapses with other neurons of the retina. Though photoreceptor diameter is only 3-8u, its length from the tip of the outer segment to the synapse may be as great as 200μ. This peculiar linear cell morphology poses special logistical problems and has evoked interesting solutions for numerous cell functions. For example, the outer segment membranes turn over by means of a unique mechanism in which new disks are continuously added at the proximal base of the outer segment, while effete disks are discarded at the tip and phagocytosed by the retinal pigment epithelium. Outer segment proteins are synthesized in the Golgi near the nucleus and must be transported north through the inner segment to their sites of assembly into the outer segment, while synaptic proteins must be transported south through the axon to the synapse.The role of the cytoskeleton in photoreceptor motile processes is being intensely investigated in several laboratories.

Download Full-text

The Role of Lymphangiogenesis in Orthotopic Prostatic Tumor-Environment on Regional and Systemic Metastasis

10.21236/ada502513 ◽

2008 ◽

Author(s):

Jeremy B. Burton

Keyword(s):

Systemic Metastasis ◽

Tumor Environment ◽

Prostatic Tumor

Download Full-text

Microglia in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200212155234 ◽

2020 ◽

Vol 17 (1) ◽

pp. 29-43 ◽

Cited By ~ 3

Author(s):

Patrick Süß ◽

Johannes C.M. Schlachetzki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Imaging Techniques ◽

Amyloid Β ◽

Disease Stage ◽

Disease Modifying Therapy ◽

Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

Download Full-text

Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance

Gut ◽

10.1136/gutjnl-2020-321731 ◽

2020 ◽

pp. gutjnl-2020-321731

Author(s):

Dominik Aschenbrenner ◽

Maria Quaranta ◽

Soumya Banerjee ◽

Nicholas Ilott ◽

Joanneke Jansen ◽

...

Keyword(s):

Mononuclear Cells ◽

Personalised Medicine ◽

Mononuclear Phagocytes ◽

Cytokine Network ◽

Peripheral Blood Mononuclear ◽

Transcriptional Signature ◽

Inflammatory Monocytes ◽

Transcriptomic Signature ◽

Inflammatory Bowel

ObjectiveDysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine.DesignWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples.ResultsWe characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.ConclusionOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.

Download Full-text

EpCAM promotes endosomal modulation of the cortical RhoA zone for epithelial organization

Nature Communications ◽

10.1038/s41467-021-22482-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Cécile Gaston ◽

Simon De Beco ◽

Bryant Doss ◽

Meng Pan ◽

Estelle Gauquelin ◽

...

Keyword(s):

Cell Shape ◽

Specific Protein ◽

Cell Polarization ◽

Stress Fiber ◽

Fiber Formation ◽

Endosomal Trafficking ◽

Transient Zone ◽

And Behavior ◽

Fine Tune

AbstractAt the basis of cell shape and behavior, the organization of actomyosin and its ability to generate forces are widely studied. However, the precise regulation of this contractile network in space and time is unclear. Here, we study the role of the epithelial-specific protein EpCAM, a contractility modulator, in cell shape and motility. We show that EpCAM is required for stress fiber generation and front-rear polarity acquisition at the single cell level. In fact, EpCAM participates in the remodeling of a transient zone of active RhoA at the cortex of spreading epithelial cells. EpCAM and RhoA route together through the Rab35/EHD1 fast recycling pathway. This endosomal pathway spatially organizes GTP-RhoA to fine tune the activity of actomyosin resulting in polarized cell shape and development of intracellular stiffness and traction forces. Impairment of GTP-RhoA endosomal trafficking either by silencing EpCAM or by expressing Rab35/EHD1 mutants prevents proper myosin-II activity, stress fiber formation and ultimately cell polarization. Collectively, this work shows that the coupling between co-trafficking of EpCAM and RhoA, and actomyosin rearrangement is pivotal for cell spreading, and advances our understanding of how biochemical and mechanical properties promote cell plasticity.

Download Full-text

Bringing high spatial resolution to the far-infrared

Experimental Astronomy ◽

10.1007/s10686-021-09719-7 ◽

2021 ◽

Author(s):

Hendrik Linz ◽

Henrik Beuther ◽

Maryvonne Gerin ◽

Javier R. Goicoechea ◽

Frank Helmich ◽

...

Keyword(s):

Spatial Resolution ◽

Formation Process ◽

Far Infrared ◽

Main Theme ◽

Spatially Resolved ◽

Research Areas ◽

External Galaxies ◽

Emergence Of Life ◽

Fine Structure Lines

AbstractThe far-infrared (FIR) regime is one of the wavelength ranges where no astronomical data with sub-arcsecond spatial resolution exist. None of the medium-term satellite projects like SPICA, Millimetron, or the Origins Space Telescope will resolve this malady. For many research areas, however, information at high spatial and spectral resolution in the FIR, taken from atomic fine-structure lines, from highly excited carbon monoxide (CO), light hydrides, and especially from water lines would open the door for transformative science. A main theme will be to trace the role of water in proto-planetary discs, to observationally advance our understanding of the planet formation process and, intimately related to that, the pathways to habitable planets and the emergence of life. Furthermore, key observations will zoom into the physics and chemistry of the star-formation process in our own Galaxy, as well as in external galaxies. The FIR provides unique tools to investigate in particular the energetics of heating, cooling, and shocks. The velocity-resolved data in these tracers will reveal the detailed dynamics engrained in these processes in a spatially resolved fashion, and will deliver the perfect synergy with ground-based molecular line data for the colder dense gas.

Download Full-text

Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages

Nature Communications ◽

10.1038/s41467-020-20315-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yawei Wang ◽

Binlin Tang ◽

Lei Long ◽

Peng Luo ◽

Wei Xiang ◽

...

Keyword(s):

Adipose Tissue ◽

Oxidative Phosphorylation ◽

Near Infrared ◽

Mitochondrial Metabolism ◽

Diet Induced Obesity ◽

Adipose Tissue Macrophages ◽

Inflammatory Activation ◽

Treatment Of Obesity ◽

Pharmaceutical Agents

AbstractPro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

Download Full-text

501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0501 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A536-A536

Author(s):

Juan Dong ◽

Cassandra Gilmore ◽

Hieu Ta ◽

Keman Zhang ◽

Sarah Stone ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Signaling Pathways ◽

Immune Checkpoint ◽

Suppressor Cells ◽

Myeloid Cell ◽

Myeloid Derived Suppressor Cells ◽

Checkpoint Protein ◽

Suppressive Function

BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

Download Full-text