• Animals
• Fibroblasts/metabolism
• Fibroblasts/drug effects
• beta Catenin/metabolism
• Mice
• Humans
• Wnt Signaling Pathway/drug effects
• Bleomycin/adverse effects
• Axin Protein/metabolism
• Axin Protein/genetics
• Male
• Idiopathic Pulmonary Fibrosis/metabolism
• Idiopathic Pulmonary Fibrosis/pathology
• Idiopathic Pulmonary Fibrosis/chemically induced
• Idiopathic Pulmonary Fibrosis/drug therapy
• Glycogen Synthase Kinase 3 beta/metabolism
• Cell Proliferation/drug effects
• Cell Differentiation/drug effects
• Lung/pathology
• Lung/metabolism
• Lung/drug effects
• Pulmonary Fibrosis/metabolism
• Pulmonary Fibrosis/chemically induced
• Pulmonary Fibrosis/drug therapy
• Pulmonary Fibrosis/pathology
• Fatty Acid Synthases/metabolism
• Fatty Acid Synthases/antagonists & inhibitors
• Autophagy/drug effects
• Mice, Inbred C57BL
• Cell Line
• Myofibroblasts/metabolism
• Female
• Cell Movement/drug effects

• The Ministry of Science and Technology
• Key R&D Program of Henan province
• Zhongyuan scholar
• Henan Project of Science and Technology

• Humans
• Neurons/metabolism
• Neuroglia/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Brain Injuries, Traumatic/metabolism
• Brain Injuries, Traumatic/pathology
• Brain Injuries, Traumatic/genetics
• Optical Imaging/methods
• Cell Communication
• Astrocytes/metabolism
• Fatty Acids/metabolism

• National Institutes of Health
• U.S. Department of Defense
• Dartmouth College
• Dartmouth Cancer Center
• Data Intensive Studies Center at Tufts University

• Astrocytoma
• Gene expression
• Glioblastoma
• Glycolysis
• Oxidative phosphorylation

• Cancer
• Cell biology
• Model organism
• Molecular biology
• Sequence analysis

• P30 CA016086 NCI NIH HHS
• UL1 TR002489 NCATS NIH HHS
• F31 NS120459 NINDS NIH HHS
• R01 NS088219 NINDS NIH HHS
• R01 NS102627 NINDS NIH HHS
• R01 NS106227 NINDS NIH HHS
• UM1 TR004406 NCATS NIH HHS
• P30 DK034987 NIDDK NIH HHS

• dietary modifications
• malnutrition
• nutrient dependency
• pediatric cancer
• precision nutrition

• CONCORD-3 study
• Erucic acid
• Glial tumors
• Glioblastoma
• PPARs
• Prevention

• Animals
• Female
• Humans
• Child
• Glioblastoma
• Medulloblastoma
• Erucic Acids
• Plant Oils
• Diet
• Brain Neoplasms/epidemiology
• Brain Neoplasms/prevention & control
• Cerebellar Neoplasms
• China/epidemiology

• OXPHOS (oxidative phosphorylation)
• ROS
• glutamine/glutamate (GABA) cycle
• metabolism
• warburg effect

Medulloblastomas (MBs) are the most prevalent brain tumours in children. They are classified as grade IV, the highest in malignancy, with about 30% metastatic tumours at the time of diagnosis. Cancer stem cells (CSCs) are a small subset of tumour cells that can initiate and support tumour growth. In MB, CSCs contribute to tumour initiation, metastasis, and therapy resistance. Metabolic differences among the different MB groups have started to emerge. Sonic hedgehog tumours show enriched lipid and nucleic acid metabolism pathways, whereas Group 3 MBs upregulate glycolysis, gluconeogenesis, glutamine anabolism, and glutathione-mediated anti-oxidant pathways. Such differences impact the clinical behaviour of MB tumours and can be exploited therapeutically. In this review, we summarise the existing knowledge about metabolic rewiring in MB, with a particular focus on MB-CSCs. Finally, we highlight some of the emerging metabolism-based therapeutic strategies for MB.

• Medulloblastoma
• Cancer stem cells
• Stemness
• Metabolism
• Glycolysis
• Lipids

• CK2
• SMO
• W535L mutation
• constitutive activation
• medulloblastoma

• Casein Kinase II/genetics
• Casein Kinase II/metabolism
• Cerebellar Neoplasms/drug therapy
• Cerebellar Neoplasms/genetics
• Cerebellar Neoplasms/metabolism
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Humans
• Medulloblastoma/drug therapy
• Medulloblastoma/genetics
• Medulloblastoma/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction
• Smoothened Receptor/genetics
• Smoothened Receptor/metabolism
• Smoothened Receptor/therapeutic use

• The National Key Research and Development Program of China
• The National Natural Science Foundation of China

• Brain tumor
• Exosome
• Medulloblastoma
• microRNA

The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

• MYCN
• PROTACs
• immunotherapy
• medulloblastoma
• metabolism
• targeted therapy

Medulloblastoma (MB) is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, but assessments in Saudi Arabian (SA)-MB cases are sparse. MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3), and Group 4 (G4) tumors. The WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signaling, whilst G3/G4 tumors show recurrent chromosomal alterations. Given that each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. Here, we performed the first assessment of MB-DNA methylation patterns in an SA cohort using archival biopsy material (FPPE n = 49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3, and G4). Furthermore, methylation analysis was able to reclassify tumors that could not be sub-grouped through next-generation sequencing, highlighting its superior accuracy for MB molecular classifications. Independent assessments demonstrated known clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates, and a large number of tumor-associated deaths. Taking our results together, we demonstrate that DNA methylation profiling enables the robust sub-classification of four disease sub-groups in archival FFPE biopsy material from SA-MB patients. Moreover, we show that the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.

• medulloblastoma
• methylation
• neuro-oncology
• non-glial
• pediatric

• cancer metabolism
• pediatric cancer
• glycolysis
• oxidative phosphorylation
• amino acid metabolism

• Sonic Hedgehog
• hypoxia-inducible factor 1a
• medulloblastoma
• reactive oxygen species
• stem cells

• Wnt signaling
• dietary restriction
• longevity
• microRNA

• epithelial-mesenchymal transition
• fatty acid synthase
• gastric cancer
• metastasis

Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4), which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA) is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C) may be more appropriate than LDHA inhibition alone.

• LDHA
• Warburg effect
• aerobic glycolysis
• lactate dehydrogenase
• medulloblastoma
• oxamate

• Cancer
• Cytomegalovirus
• Immunotherapy
• Medulloblastoma
• Pediatric

Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

• autophagy
• biosynthesis
• brain tumors
• cancer
• catabolism
• glioma
• metabolism
• mitochondria

Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of Medulloblastoma, the most frequent pediatric brain tumor. We show here that the energy sensor AMPK inhibits Hh signaling by phosphorylating a single residue of human Gli1 that is not conserved in other species.

Studies with selective agonists and genetic deletion have revealed that AMPK activation inhibits canonical Hh signaling in human, but not in mouse cells. Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. Notably, we show that selective AMPK activation inhibits Gli1-driven proliferation and that this effect is linked to Ser408 phosphorylation, which represents a key metabolic checkpoint for Hh signaling.

Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors.

• AMPK
• Gli1
• Hedgehog
• cancer metabolism
• phosphorylation

• Angiogenesis
• E2F1
• Endothelial cell
• GSKIP
• Osteopetrosis
• PPARγ
• Pulmonary hypertension
• Wnt signaling

• Biomarker
• Colorectal cancer
• Hexokinase
• Prognosis

• 2DG, 2-deoxy-D-glucose
• 3-BrPA, 3-Bromopyruvate
• ACC, Acetyl-CoA carboxylase
• ATO, arsenic trioxide
• DCA
• DCA, dichloroacetate
• EGL, external granular layer
• GCPs, granule cells progenitors
• HH, Hedgehog
• HK2, Hexokinase 2
• Hedgehog
• IGL, internal granular layer
• MB, Medulloblastoma
• PARP, poly( ADP-ribose) polymerase
• PKM2, Pyruvate Kinase M2
• Ptch1, Patched1
• ROS, reactive oxygen species
• SHH, Sonic Hedgehog
• Smo, Smoothened
• Sufu, suppressor of fused
• cerebellum
• glycolysis
• medulloblastoma
• metabolism

The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

• Cancer therapy
• Epigenetics
• Gli
• Hedgehog
• Metabolism
• Smo

Peroxisome proliferator-activated receptor γ (PPAR γ), a member of the nuclear receptor superfamily, is a ligand-activated transcription factor that plays an important role in the control of a variety of physiological processes. The last decade has witnessed an increasing interest for the role played by the agonists of PPAR γ in antiangiogenesis, antifibrosis, anti-inflammation effects and in controlling oxidative stress response in various organs. As the pathologic mechanisms of major blinding diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), keratitis, and optic neuropathy, often involve neoangiogenesis and inflammation- and oxidative stress-mediated cell death, evidences are accumulating on the potential benefits of PPAR γ to improve or prevent these vision threatening eye diseases. In this paper we describe what is known about the role of PPAR γ in the ocular pathophysiological processes and PPAR γ agonists as novel adjuvants in the treatment of eye diseases.

HEDGEHOG (HH) signaling is a key regulator of tissue development and its aberrant activation is involved in several cancer types, including melanoma. We and others have shown a reciprocal cross talk between HH signaling and p53, whose function is often impaired in melanoma. Here we present evidence that both GLI1 and GLI2, the final effectors of HH signaling, regulate the transcription factor E2F1 in melanoma cells, by binding to a functional non-canonical GLI consensus sequence. Consistently, we find a significant correlation between E2F1 and PATCHED1 (PTCH1), GLI1 and GLI2 expression in human melanomas. Functionally, we find that E2F1 is a crucial mediator of HH signaling and it is required for melanoma cell proliferation and xenograft growth induced by activation of the HH pathway. Interestingly, we present evidence that the HH/GLI-E2F1 axis positively modulates the inhibitor of apoptosis-stimulating protein of p53 (iASPP) at multiple levels. HH activation induces iASPP expression through E2F1, which directly binds to iASPP promoter. HH pathway also contributes to iASPP function, by the induction of Cyclin B1 and by the E2F1-dependent regulation of CDK1, which are both involved in iASPP activation. Our data show that activation of HH signaling enhances proliferation in presence of E2F1 and promotes apoptosis in its absence or upon CDK1 inhibition, suggesting that E2F1/iASPP dictates the outcome of HH signaling in melanoma. Together, these findings identify a novel HH/GLI-E2F1-iASPP axis that regulates melanoma cell growth and survival, providing an additional mechanism through which HH signaling restrains p53 proapoptotic function.

E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general ‘multi-purpose’ cell fate genes but can execute tissue- and cell type-specific gene regulatory programs.

• E2F transcription factors
• cell cycle
• epigenetics
• neural precursor cell (NPC)
• pocket proteins
• stem cell fate
• stem cells
• transcription

• Aerobic glycolysis
• Cerebellar development
• Hexokinase 2
• Medulloblastoma
• PkM2
• Postnatal neurogenesis

• Animals
• Cell Proliferation
• Cerebellar Neoplasms/metabolism
• Cerebellar Neoplasms/pathology
• Cerebrum/physiology
• E2F Transcription Factors/metabolism
• Energy Metabolism/physiology
• Glycolysis/physiology
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Hexokinase/biosynthesis
• Hexokinase/genetics
• Hexokinase/metabolism
• Humans
• Intracellular Signaling Peptides and Proteins/metabolism
• Lipid Metabolism/physiology
• Lipids/biosynthesis
• Lipogenesis/physiology
• Medulloblastoma/metabolism
• Medulloblastoma/pathology
• Mice
• Neurogenesis/physiology
• PPAR gamma/metabolism
• Pyruvate Kinase/biosynthesis
• Pyruvate Kinase/genetics
• Pyruvate Kinase/metabolism

• K08 NS077978 NINDS NIH HHS
• P30 NS045892 NINDS NIH HHS
• R01 NS088219 NINDS NIH HHS
• 1K08NS077978-01 NINDS NIH HHS

• Medulloblastoma
• eukaryotic elongation factor 2 kinase (eEF2K)
• glycolysis
• lipogenesis

• Biomarkers
• Cancer stem/progenitor cells
• Cancer-initiating cells
• Epithelial–mesenchymal transition
• Hypoxia
• Metabolic pathways
• Metastases
• Metastasis-initiating cells
• Multitargeted therapies
• Personalized medicine
• Therapeutic targets

• Animals
• Cellular Reprogramming
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Genes, Neoplasm
• Humans
• Molecular Targeted Therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/therapy
• Neoplastic Stem Cells/metabolism
• Signal Transduction

• R01 CA138791 NCI NIH HHS
• U54 CA163120 NCI NIH HHS
• UO1 CA111294 NCI NIH HHS

• expression profiling
• hedgehog
• medulloblastoma
• targeted therapy

• Cerebellar Neoplasms/genetics
• Cerebellar Neoplasms/therapy
• Gene Expression Profiling
• Hedgehog Proteins/metabolism
• Humans
• Medulloblastoma/genetics
• Medulloblastoma/therapy
• Molecular Targeted Therapy
• Receptors, G-Protein-Coupled/genetics
• Signal Transduction/genetics
• Signal Transduction/physiology
• Smoothened Receptor

Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRAS^G12D during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRAS^G12D expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing the inducible oncogenic KRAS^G12D line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRAS^G12D showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch pathways. Increase in TGFβ, following KRAS^G12D activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.

• KRAS
• Medulloblastoma
• Notch
• Pancreatic adenocarcinoma
• Reporters
• Shh
• TGFβ
• Zebrafish

• Cerebellar development
• Granule cell precursors
• Medulloblastoma
• Patched1
• Preneoplastic lesion
• Sonic hedgehog

• Animals
• Animals, Newborn
• Cerebellum/growth & development
• Cerebellum/metabolism
• Cerebellum/pathology
• Genotype
• Heterozygote
• Immunohistochemistry
• Ki-67 Antigen/metabolism
• Medulloblastoma/metabolism
• Medulloblastoma/pathology
• Mice
• Mice, Knockout
• Patched Receptors
• Patched-1 Receptor
• Precancerous Conditions/genetics
• Precancerous Conditions/metabolism
• Precancerous Conditions/pathology
• Receptors, Cell Surface/genetics

• cancer metabolism
• idh1/2
• pkm2
• myc
• succinate dehydrogenase
• fumarate hydratase

• Cell Proliferation
• Fumarate Hydratase/genetics
• Fumarate Hydratase/metabolism
• Glycolysis
• Humans
• Isocitrate Dehydrogenase/genetics
• Isocitrate Dehydrogenase/metabolism
• Molecular Targeted Therapy
• Mutation
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Pyruvate Kinase/genetics
• Pyruvate Kinase/metabolism
• Succinate Dehydrogenase/genetics
• Succinate Dehydrogenase/metabolism

• Y99 CA999999 NCI NIH HHS
• Z99 CA999999 Intramural NIH HHS
• ZIA BC011028-05 Intramural NIH HHS
• ZIA BC011038-05 Intramural NIH HHS