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Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 and depleting tumor stem cell populations

ABSTRACT: Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 and depleting tumor stem cell populations

PROVIDER: PRJNA786600 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17144672_1.fastq.gz	Fastqsanger.gz
	SRR17144672_2.fastq.gz	Fastqsanger.gz
	SRR17144673_1.fastq.gz	Fastqsanger.gz
	SRR17144673_2.fastq.gz	Fastqsanger.gz
	SRR17144674_1.fastq.gz	Fastqsanger.gz

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AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-kB activation

Project description:Background: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown. Results: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-kB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-kB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells. Conclusions: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-kB. AMPK-NF-kB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-kB and Shh pathways confers synergy for SHH-MB therapy.

2023-07-01 | GSE218076 | GEO

Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 and depleting tumor stem cell populations

Project description:We report scRNA-seq data showing the effect of Prkaa1/2 deletion on medulloblastomas that form in Smo-mutant mice. We generate tumor-bearing mice by breeding hGFAP-Cre/Prkaa1fl/fl/Prk112fl/fl and Prkaa1fl/fl/Prk112fl/fl/SmoM2 mouse lines to prodce tumor-prone progeny with homozygous, conditional deletion of Prkaa1 and Prkaa2 (G-SmoAMPK mice). We compared tumors from G-Smo mice withintact Prkaa1 and Prkaa2 to tumors from G-SmoAMPK mice, using Drop-seq-based scRNA-seq.

2021-12-08 | GSE190297 | GEO

mTORC1 to AMPK Switching Underlies β-Cell Metabolic Plasticity During Maturation and Diabetes

Project description:Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). The molecular mechanisms driving this maturation of β-cell function remain incompletely understood. Here, we show that the control of cellular signaling in β-cells fundamentally switches from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this is critical for functional maturation. Moreover, AMPK is activated by the dietary transition taking place during weaning, and this in turn inhibits mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegates them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling is sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also show that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, is associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.

2019-06-06 | GSE132261 | GEO

mTORC1 promotes malignant large cell/anaplastic histology and is a therapeutically targetable vulnerability in SHH-TP53 mutant medulloblastoma

Project description:Distinct molecular subgroups and subtypes have been identified for medulloblastoma (MB), one of the most malignant brain tumors of childhood, with the sonic hedgehog (SHH)-activated subgroup of patients with mutations in p53 having a very severe outcome, associated with unfavorable histological large cell/anaplastic (LC/A) features. Aim of this study was to determine whether hyperactivation of mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway, whose role in molecular subtypes of MB is currently undefined, underlies the acquisition of LC/A histology in this subtype. MBs developing in p53-deficient Ptch+/- SHH mice show LC/A features that correlate with mTORC1 hyperactivation, which, mechanistically, is mediated by a decrease in the p53-dependent expression of the negative mTORC1 regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promotes the acquisition of the LC/A phenotype. Furthermore, mTORC1 inhibition in both autochthonous p53-mutant SHH MBs and CSC-derived LC/A MBs results in reduced tumor burden and enhanced survival. Most remarkably, mTORC1 hyperactivation in tumor cells is detected only in human p53-mutant SHH MB samples and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreases tumor growth and malignancy. As such, mTORC1 may act as a new and specific druggable target for this subset of SHH MB, thus resulting in the implementation of a more stringent MB risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.

2021-10-21 | GSE183901 | GEO

mTORC1/AMPK responses define a core gene set for developmental cell fate switching

Project description:The kinases mTORC1 and AMPK are at the nexus of nutrient responses and control of cellular growth. However, responses to nutrient loss are complex and affect multiple transcriptional pathways. We are interested in the mTORC1-directed regulation of transcription networks that specifically regulate developmental decisions. Dictyostelium grow logarithmically as single cells in nutrient-rich media, but, upon nutrient withdrawal, growth ceases and cells enter a program for multi-cellular development. Within 30 minutes of starvation, >4,000 genes show significant (p<0.05) changes in gene expression patterns. However, we hypothesize that not all these gene changes are required for development and that many expression changes reflect stress response to a media shift supplementary to nutrient loss, apart from developmental effects. We, thus, sought ways to promote development in the absence of nutrient loss, to better focus on developmentally essential gene sets. Since kinases mTORC1 and AMPK function as nutrient and energy sensors, we first examined their relative activities in Dictyostelium during phases of rapid growth and starvation-induced development. We found that these kinases exhibited reciprocal patterns of activation under various conditions. With this knowledge, we identified rich media conditions that permitted rapid cell growth, but a growth/development switch upon the directed and reciprocal inactivation/activation of mTORC1/AMPK. Examination of gene expression under conditions of development in nutrient-rich media indicated that changes in expression of most starvation-regulated genes were not required for development. Our data suggest that the up-regulation of ~300 genes defines essential early signaling pathways for developmental induction, integrating cAMP/PKA circuitries and including many unclassified genes.

2019-05-22 | GSE123599 | GEO

Expression data from MOLM-14 human acute myeloid leukemia cell line after AMPK activation by GSK621 according to mTORC1 activation level

Project description:AMPK activation by GSK621 induces cell death in acute myeloid leukemia. Surprisingly, we found that mTORC1 inhibition with rapamycin protects cells against GSK621-induced cytotoxicity. A genome-wide gene expression assay was performed to understand the molecular basis of this phenotype.

2016-04-22 | GSE68209 | GEO

RNA-seq of metformin treatment in liver in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null

Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high fat diet treated with metformin was largely ablated by AMPK-deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.

2023-08-10 | GSE157049 | GEO

RNA-seq of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment.

2023-08-10 | GSE157048 | GEO

AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-kB activation

Project description:AMPK attenuates SHH subgroup medulloblastoma growth and metastasis by inhibiting NF-kB activation

| PRJNA902278 | ENA

Ribosome profiling of metformin treatment in primary murine hepatocytes in WT, Raptor Ser-Ala mutant, Tsc2-null, Raptor mutant;Tsc2-null, and Ampk-null cells

Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the translational response to metformin.

2023-08-10 | GSE157050 | GEO

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