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1.
Nano Lett ; 23(23): 10687-10695, 2023 Dec 13.
Article in English | MEDLINE | ID: mdl-37889874

ABSTRACT

Dysregulated lipid metabolism contributes to neurodegenerative pathologies and neurological decline in lysosomal storage disorders as well as more common neurodegenerative diseases. Niemann-Pick type A (NPA) is a fatal neurodegenerative lysosomal storage disease characterized by abnormal sphingomyelin accumulation in the endolysosomal lumen. The ability to monitor abnormalities in lipid homeostasis intracranially could improve basic investigations and the development of effective treatment strategies. We investigated the carbon nanotube-based detection of intracranial lipid content. We found that the near-infrared emission of a carbon nanotube-based lipid sensor responds to lipid accumulation in neuronal and in vivo models of NPA. The nanosensor detected lipid accumulation intracranially in an acid sphingomyelinase knockout mouse via noninvasive near-infrared spectroscopy. This work indicates a tool to improve drug development processes in NPA, other lysosomal storage diseases, and neurodegenerative diseases.


Subject(s)
Lysosomal Storage Diseases , Nanotubes, Carbon , Neurodegenerative Diseases , Animals , Mice , Lysosomal Storage Diseases/pathology , Sphingomyelins , Neurons/metabolism , Lysosomes/metabolism
2.
Int J Radiat Oncol Biol Phys ; 117(4): 955-965, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37244631

ABSTRACT

PURPOSE: To determine the mechanisms involved in partial volume radiation therapy (RT)-induced tumor response. METHODS AND MATERIALS: We investigated 67NR murine orthotopic breast tumors in Balb/c mice and Lewis lung carcinoma (LLC cells; WT, Crispr/Cas9 Sting KO, and Atm KO) injected in the flank of C57Bl/6, cGAS, or STING KO mice. RT was delivered to 50% or 100% of the tumor volume using a 2 × 2 cm collimator on a microirradiator allowing precise irradiation. Tumors and blood were collected at 6, 24, and 48 hours post-RT and assessed for cytokine measurements. RESULTS: There is a significant activation of the cGAS/STING pathway in the hemi-irradiated tumors compared with control and to 100% exposed 67NR tumors. In the LLC model, we determined that an ATM-mediated noncanonical activation of STING is involved. We demonstrated that the partial exposure RT-mediated immune response is dependent on ATM activation in the tumor cells and on the STING activation in the host, and cGAS is dispensable. Our results also indicate that partial volume RT stimulates a proinflammatory cytokine response compared with the anti-inflammatory profile induced by 100% tumor volume exposure. CONCLUSIONS: Partial volume RT induces an antitumor response by activating STING, which stimulates a specific cytokine signature as part of the immune response. However, the mechanism of this STING activation, via the canonical cGAS/STING pathway or a noncanonical ATM-driven pathway, depends on the tumor type. Identifying the upstream pathways responsible for STING activation in the partial RT-mediated immune response in different tumor types would improve this therapy and its potential combination with immune checkpoint blockade and other antitumor therapies.

3.
Br J Cancer ; 121(5): 384-394, 2019 08.
Article in English | MEDLINE | ID: mdl-31363169

ABSTRACT

BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.


Subject(s)
Adrenal Cortex Neoplasms/genetics , Adrenocortical Carcinoma/genetics , E2F1 Transcription Factor/genetics , Enhancer of Zeste Homolog 2 Protein/genetics , Gene Expression Regulation, Neoplastic , Adenosine/analogs & derivatives , Adenosine/pharmacology , Animals , Cell Cycle Proteins/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Chromatin Immunoprecipitation , Computational Biology , Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors , Humans , Indoles/pharmacology , Mice, Knockout , Multivariate Analysis , Proportional Hazards Models , Ribonucleoside Diphosphate Reductase/antagonists & inhibitors , Ribonucleoside Diphosphate Reductase/genetics , Securin/genetics
4.
Proc Natl Acad Sci U S A ; 115(52): E12265-E12274, 2018 12 26.
Article in English | MEDLINE | ID: mdl-30541888

ABSTRACT

Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.


Subject(s)
Adrenal Cortex/enzymology , Cyclic AMP-Dependent Protein Kinase RIbeta Subunit/metabolism , Enhancer of Zeste Homolog 2 Protein/metabolism , Signal Transduction , Adrenal Cortex/metabolism , Animals , Cell Differentiation , Cyclic AMP-Dependent Protein Kinase RIbeta Subunit/genetics , Cyclic Nucleotide Phosphodiesterases, Type 1/genetics , Cyclic Nucleotide Phosphodiesterases, Type 1/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 3/genetics , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 7/genetics , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Female , Male , Mice, Inbred C57BL , Mice, Knockout , Steroids/metabolism , Zona Fasciculata/cytology , Zona Fasciculata/enzymology , Zona Fasciculata/metabolism , Zona Glomerulosa/cytology , Zona Glomerulosa/enzymology , Zona Glomerulosa/metabolism
5.
Nat Commun ; 7: 12751, 2016 09 14.
Article in English | MEDLINE | ID: mdl-27624192

ABSTRACT

Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates ß-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.


Subject(s)
Adrenal Gland Neoplasms/etiology , Cyclic AMP-Dependent Protein Kinases/metabolism , Wnt Signaling Pathway , Zona Fasciculata/metabolism , Zona Glomerulosa/metabolism , Animals , Carcinogenesis , Cell Differentiation , Cell Line, Tumor , Female , Humans , Mice , Phosphorylation , Zona Fasciculata/cytology , Zona Glomerulosa/cytology , beta Catenin/metabolism
6.
Hum Mol Genet ; 25(13): 2789-2800, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27149985

ABSTRACT

Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/ß-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC.


Subject(s)
Adrenal Cortex Neoplasms/genetics , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Adrenal Cortex Neoplasms/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Databases, Nucleic Acid , Disease Progression , Gene Expression , Genetic Predisposition to Disease/genetics , Humans , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Mice , Mice, Transgenic , RNA Interference , Risk Factors , Wnt Signaling Pathway , beta Catenin/genetics
7.
Mol Cell Endocrinol ; 408: 156-64, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-25542843

ABSTRACT

The adrenal cortex plays essential roles in the control of sodium and water homeostasis, stress response, inflammation and metabolism, through secretion of glucocorticoids and mineralocorticoids. Coordinated production of these hormones relies on functional zonation of the cortex, characterised by expression of Cyp11b2 under the control of angiotensin II and plasma potassium level in zona glomerulosa (ZG) and Cyp11b1 under the control of ACTH in zona fasciculata (ZF). The mechanisms involved in the establishment of functional zonation and its maintenance during centripetal cortex cell renewal are still poorly understood. Here, we hypothesise that the hormonal and signalling pathways that control adrenal cortex function are also involved in cortical zonation. In particular, we summarise evidence on the role of WNT/ß-catenin signalling in ZG differentiation and how tight control of its activity is required to shape the adult cortex. In this context, we discuss the potential role of known WNT regulators and the possibility of a reciprocal cross-talk between PKA and WNT signalling.


Subject(s)
Adrenal Cortex/metabolism , Homeostasis , Wnt Proteins/metabolism , Adrenal Cortex/cytology , Animals , Cell Self Renewal , Humans , Models, Biological , Signal Transduction
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