scholarly journals Distinct roles of glutamine metabolism in benign and malignant cartilage tumors with IDH mutations

2021 ◽  
Author(s):  
Hongyuan Zhang ◽  
Vijitha Puviindran ◽  
Puviindran Nadesan ◽  
Xiruo Ding ◽  
Leyao Shen ◽  
...  
Keyword(s):  
Essential Amino Acids ◽  
Tumor Burden ◽  
Glutamine Metabolism ◽  
Genetic Mutations ◽  
Chondrocyte Proliferation ◽  
Lesion Development ◽  
Human Chondrosarcoma ◽  
Hypertrophic Chondrocyte ◽  
Idh Mutations ◽  
Cartilage Tumors

AbstractEnchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Chondrocytes and chondrosarcomas with mutations in the IDH1 or IDH2 genes showed enhanced glutamine utilization in downstream metabolism. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. Pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. In human chondrosarcoma, glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study reveals that glutamine metabolism can play distinct roles in benign and malignant cartilage tumors sharing the same genetic mutations. Inhibiting GLS may provide a therapeutic approach to suppress chondrosarcoma tumor growth.

16. Physiological effects of IDH1 loss-of-function on Chondrocyte Differentiation through Hedgehog Pathway upregulation

2018 ◽  
Author(s):  
Cassie Tyson
Keyword(s):  
Developmental Stages ◽  
Hedgehog Pathway ◽  
Chondrocyte Differentiation ◽  
Loss Of Function ◽  
Wild Type ◽  
Phenotypic Analysis ◽  
Growth Plate Chondrocytes ◽  
Idh Mutations ◽  
Cartilage Tumors ◽  
Deficient Mice

Cartilage tumors are the most common and terminal primary neoplasms in bone. Physiologically, bones formed through endochondral ossification are regulated by the Hedgehog pathway and Parathyroid hormone-like hormone feedback loop. The upregulation of the infamous Hedgehog pathway has been demonstrated in several non-cartilaginous neoplasms. Recently, frequent mutational events of isocitrate dehydrogenase1 (IDH1) were identified in cartilage tumors. In other neoplasms, IDH mutations produces an oncometabolite that can promote HIF1a activation, contributing to tumorigenesis. Currently, the role of IDH1 mutations in cartilage tumors remain unknown. Investigating the physiological aspect of IDH1proves useful in identifying novel therapeutic targets for cartilage tumors. IDH1 deficient and wild-type littermates, were harvested for forelimbs and hindlimbs at various developmental stages for phenotypic analysis via hematoxylin and eosin staining. Histological analysis demonstrated IDH1 homozygous deficient mice at embryonic stages exhibited dwarfism and an elongated layer of hypertrophic chondrocytes. This was verified via immunohistochemistry Type 10 Collagen staining and Quantitative PCR (qPCR) using the chondrocyte terminal differentiation marker Col10a1. Whole skeletons of IDH1 deficient mice were subjected to skeletal double staining which demonstrated delayed mineralization of underdeveloped IDH1 deficient mice contrasted with wild-type littermates. qPCR was performed to examine the status of chondrocyte differentiation through the Hedgehog pathway in cultured primarymouse growth plate chondrocytes. Interestingly, IDH1 deficient non-neoplastic cells revealed significant upregulation of Hedgehog target molecules in IDH1 deficient chondrocytes. As a result, the loss-offunction of IDH1 was identified as a potential impairment of chondrocyte differentiation and a factor towards chondrocyte tumorgenisis.

scholarly journals Mutant IDH is sufficient to initiate enchondromatosis in mice

2015 ◽  
Vol 112 (9) ◽  
pp. 2829-2834 ◽  
Author(s):  
Makoto Hirata ◽  
Masato Sasaki ◽  
Rob A. Cairns ◽  
Satoshi Inoue ◽  
Vijitha Puviindran ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Growth Plate ◽  
Mutant Allele ◽  
Somatic Mutations ◽  
Expression Of Genes ◽  
Idh Mutations ◽  
Neonatal Stage ◽  
Cartilage Tumors ◽  
Tumor Types

Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.

scholarly journals Driver Genetic Mutations in Spinal Cord Gliomas Direct the Degree of Functional Impairment in Tumor-Associated Spinal Cord Injury

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2525
Author(s):  
Yoshitaka Nagashima ◽  
Yusuke Nishimura ◽  
Fumiharu Ohka ◽  
Kaoru Eguchi ◽  
Kosuke Aoki ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Functional Impairment ◽  
The Body ◽  
World Health ◽  
Genetic Mutations ◽  
Idh Mutations ◽  
Cord Injury ◽  
Grade Ii ◽  
Grade Iii

Genetic analysis in glioma has been developed recently. Spinal cord glioma is less common than intracranial glioma. Thus, the clinical significance of genetic mutations in spinal cord gliomas remains unclear. Furthermore, because the spinal cord is an important communication channel between the brain and the rest of the body, increased attention should be paid to its functional prognosis. In this study, we investigated the functional prognosis and driver genetic mutations in eight patients with spinal cord gliomas (World Health Organization grade I, three cases; grade II, two cases; grade III/IV, three cases). IDH mutations were detected in all grade II cases and H3F3A mutations were detected in all grade III/IV cases. The functional status of grade I and II gliomas remained unchanged or improved 1 year after surgery, whereas grade III/IV gliomas remained unchanged or deteriorated. Spinal glioma progenitor cells with H3F3A mutations were associated with accelerated tumor-associated spinal cord injury, which led to functional impairment. Conversely, the presence of IDH mutations, which are rarely reported in spinal gliomas, indicated a relatively favorable functional prognosis.

IDH1 Mutant Inhibitor Induces Cellular Differentiation and Offers a Combination Benefit With Ara-C In a Primary Human Idh1 Mutant AML Xenograft Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3946-3946 ◽  
Author(s):  
Katharine Yen ◽  
Rene Lemieux ◽  
Janeta Popovici-Muller ◽  
Yue Chen ◽  
Hua Yang ◽  
...  
Keyword(s):  
Cellular Differentiation ◽  
Low Dose ◽  
Ex Vivo ◽  
Point Mutations ◽  
Xenograft Model ◽  
Tumor Burden ◽  
Employment Equity ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh Mutations ◽  
Equity Ownership

Abstract Somatic point mutations in isocitrate dehydrogenase 1/2 have a gain-of-function neomorphic activity that converts alpha-ketoglutarate to the oncometabolite, R (-)-2-hydroxyglutarate (2HG). Prospective studies of AML patients carrying IDH mutations have shown that intracellular concentrations of 2HG can range from 3-10 mM. This abnormal level of 2HG results in dysregulation of alpha-ketoglutarate dependent enzymes leading to alterations in the epigenetic state of hematopoietic progenitor/stem cells and functionally blocks their ability to fully differentiate. We have developed a potent and selective, orally available IDH1 mutant inhibitor AGI-14100, that is able to reduce intracellular 2HG concentrations to baseline levels found in wildtype cells. Ex vivo treatment of IDH1 mutant-containing primary human AML patient samples with AGI-14100 induced a proliferative burst followed by cellular differentiation as shown by flow cytometry and cytology. We next treated a primary human IDH1 (R132H)/FLT3-ITD mutant xenograft model with AGI-14100 either alone or in combination with Ara-c. In these studies, AGI-14100 alone significantly decreased tumor burden in the peripheral blood after 1 month of continuous BID treatment. In combination with a short-term, low-dose course of Ara-C, we also observed a decrease in the bone marrow tumor burden that was better than either treatment alone. Furthermore, this response was sustainable for >3 weeks even after dosing of both drugs had been terminated. Taken together, these data suggest that inhibition of mutant IDH1with AGI-14100 and low dose Ara-c could provide a combination benefit for patients with AML. Disclosures: Yen: Agios Pharmaceuticals: Employment, Equity Ownership. Lemieux:agios Pharmaceuticals: Employment, Equity Ownership. Popovici-Muller:agios Pharmaceuticals: Employment, Equity Ownership. Chen:agios Pharmaceuticals: Employment, Equity Ownership. Yang:Agios Pharmaceuticals: Employment, Equity Ownership. Straley:Agios Pharmaceuticals: Employment, Equity Ownership. Choe:agios Pharmaceuticals: Employment, Equity Ownership. Dorsch:agios Pharmaceuticals: Employment, Equity Ownership. Agresta:agios Pharmaceuticals: Employment, Equity Ownership. Schenkein:agios Pharmaceuticals: Employment, Equity Ownership. Biller:agios Pharmaceuticals: Employment, Equity Ownership. Su:agios Pharmaceuticals: Employment, Equity Ownership. Wang:Agios Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Targeting Glutamine Addiction in Gliomas

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 310 ◽  
Author(s):  
Marta Obara-Michlewska ◽  
Monika Szeliga
Keyword(s):  
Metabolic Pathways ◽  
Detailed Comparison ◽  
Therapeutic Strategies ◽  
Glutamine Metabolism ◽  
Metabolic Adaptation ◽  
Genetic Mutations ◽  
Malignant Phenotype ◽  
Proliferating Cells ◽  
Who Grade ◽  
Glutamine Transport

The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

scholarly journals Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rémy Nicolle ◽  
Mira Ayadi ◽  
Anne Gomez-Brouchet ◽  
Lucile Armenoult ◽  
Guillaume Banneau ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Tumor Differentiation ◽  
Cartilaginous Tissue ◽  
Clinical Value ◽  
Cell Cycle Activation ◽  
Recurrent Mutations ◽  
Idh Mutations ◽  
Cartilage Tumors ◽  
Molecular Profiles

Abstract Chondrosarcomas are primary cancers of cartilaginous tissue with highly contrasting prognoses. These tumors are defined by recurrent mutations in the IDH genes and other genetic alterations including inactivation of CDKN2A and COL2A1; however, these have no clinical value. Here we use multi-omics molecular profiles from a series of cartilage tumors and find an mRNA classification that identifies two subtypes of chondrosarcomas defined by a balance in tumor differentiation and cell cycle activation. The microRNA classification reveals the importance of the loss of expression of the 14q32 locus in defining the level of malignancy. Finally, DNA methylation is associated with IDH mutations. We can use the multi-omics classifications to predict outcome. We propose an mRNA-only classifier to reproduce the integrated multi-omics classification, and its application to relapsed tumor samples shows the progressive nature of the classification. Thus, it may be possible to use mRNA-based signatures to detect patients with high-risk chondrosarcomas.

scholarly journals Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis

2018 ◽  
Vol 115 (16) ◽  
pp. 4228-4233 ◽  
Author(s):  
He Xu ◽  
Min-Sik Lee ◽  
Pei-Yun Tsai ◽  
Ashley S. Adler ◽  
Natasha L. Curry ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Tumor Cells ◽  
Proteasome Inhibitors ◽  
Essential Amino Acids ◽  
Tumor Burden ◽  
Lung Tumorigenesis ◽  
Insulin Receptor Substrates ◽  
Effective Therapeutic Strategy

Non–small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (Irs1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with Irs1/Irs2 loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for KRAS-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in KRAS-mutant NSCLC.

scholarly journals Translational and HIF1α-dependent metabolic reprograming underpin oncometabolome plasticity and synergy between oncogenic kinase inhibitors and biguanides

2017 ◽  
Author(s):  
Laura Hulea ◽  
Simon-Pierre Gravel ◽  
Masahiro Morita ◽  
Marie Cargnello ◽  
Oro Uchenunu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Metabolic Profiling ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Essential Amino Acids ◽  
Glutamine Metabolism ◽  
Transformed Cells ◽  
Opposing Effects ◽  
Stimulation Of

AbstractThere is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI – biguanide combinations is impeded by HIF1α and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1α-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

Mutant IDH is sufficient to initiate enchondromatosis in mice

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Enzymatic Activity ◽  
Cell Cultures ◽  
Mutant Allele ◽  
Somatic Mutations ◽  
Hypertrophic Chondrocytes ◽  
Idh Mutations ◽  
Neonatal Stage ◽  
Cartilage Tumors ◽  
Tumor Types

Enchondromas are benign cartilage tumors and precursors tomalignant chondrosarcomas. Somatic mutations in the isocitratedehydrogenase genes (IDH1 and IDH2) are present in the majorityof these tumor types. How these mutations cause enchondromasis unclear. Here, we identified the spectrum of IDH mutations inhuman enchondromas and chondrosarcomas and studied theireffects in mice. A broad range of mutations was identified, includingthe previously unreported IDH1-R132Q mutation. These mutationsharbored enzymatic activity to catalyze α-ketoglutarate toD-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in oneallele in cells expressing type 2 collagen showed a disorderedgrowth plate, with persistence of type X-expressing chondrocytes.Chondrocyte cell cultures from these animals or controls showedthat there was an increase in proliferation and expression of genescharacteristic of hypertrophic chondrocytes with expression ofIdh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutantknock-in mice (mutant allele expressed in chondrocytes) did notsurvive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutantconditional knock-in mice, in which Cre was induced by tamoxifenafter weaning, developed multiple enchondroma-like lesions.Taken together, these data show that mutant IDH or D-2HG causespersistence of chondrocytes, giving rise to rests of growth-platecells that persist in the bone as enchondromas.

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