Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

2 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma

ABSTRACT: Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structureguided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h aftertreatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly toKH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancermetabolism by PGAM1 inhibition in PDAC. Also, this work provided “proof of concept” for the potential application of metabolictreatment in clinical practice.

TISSUE(S): Cell Line

SUBMITTER: Jinyan,Huang

PROVIDER: OEX001971 | NODE |

REPOSITORIES: NODE

ACCESS DATA

Json Xml

Publications

Sorry, this publication's infomation has not been loaded in the Indexer, please go directly to PUBMED or Altmetric.

Similar Datasets

BMI Expression is Required for Pancreatic Cancer Progression

Project description:Pancreatic cancer is one of the deadliest human malignancies, with a survival rate less than 10%. Traditional modes of therapy have proven ineffective in the treatment of pancreatic cancer, highlighting the need to further understand the basic biology of the disease in order to identify new treatment modalities. Previously, our group showed that the epigenetic regulator Bmi1 is required for the initiation of pancreatic cancer in mice. In murine models of PDAC, mice lacking pancreatic Bmi1 expression do not develop precancerous lesions, despite oncogene expression. In this work, we sought to determine the role of Bmi1 in later stages of pancreatic tumor development. Using a CRISPR/Cas9 strategy, we deleted Bmi1 in primary human pancreatic caner cells and created clonal lines. When used in a subcutaenous tumor growth assay, those cells lacking BMI1 expression formed tumors that grew significantly smaller than controls. To query the mechanism of BMI1 action in pancreatic cancer growth, we used RNA sequencing to compare those pancreatic cancer cells with and without BMI1 expressed. This revealed that Bmi1 controls the gene expression of glycolysis and cell proliferation pathways, likely the reason for its requirement in pancreatic tumor growth. Overall, we found that Bmi1 is required in pancreatic tumor progression, and that it controls gene expression in both glycolysis and cell proliferation.

2023-06-30 | GSE149981 | GEO

Differential expression of metabolic genes in tumor and stromal components in primary and metastatic loci in pancreatic adenocarcinomas

Project description:Background:Pancreatic cancer is the fourth leading cause of cancer related deaths the United States with a five-year survival rate of 6% (1). It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions (2-5). However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma. Methods and Findings:We analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism) expression profiles of primary and metastatic lesions from 35 pancreatic cancer patients by Affymetrix expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC) analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites. Conclusions: Here, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer. Furthermore, we identify key metabolic genes that can be targeted to diminish overall cancer progression and others that can be targeted to prevent cancer metastasis at specific organ sites. reference x sample

2012-04-28 | E-GEOD-34153 | biostudies-arrayexpress

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Project description:Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

2019-04-10 | PXD012979 | Pride

pbSMARCD3 is a key epigenetic dependency for pancreatic adenocarcinoma

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by extensive resistance to conventional therapies, making clinical management a significant challenge. As cancer progresses, developmental signals are often aberrantly re-activated, driving the self-renewal of cancer cells and fueling therapy resistance. To understand the epigenetic regulators that may be required to sustain these aggressive cells, we carried out a focused screen and identified SMARCD3 as a new functional dependency in pancreatic cancer. SMARCD3, a subunit of the SWI/SNF nucleosome remodeling complex, was uniquely up-regulated in PDAC stem cells and amplified in human cancer. Using a dual-recombinase model of pancreatic cancer, we showed that stage-specific conditional genetic deletion of Smarcd3 preferentially impaired growth of established tumors, improving survival and synergizing with chemotherapy. Consistent with this, SMARCD3 was required for the in vivo propagation of patient-derived xenografts. Mechanistically, we found that SMARCD3 is incorporated in the BAF complex variant of SWI/SNF. Using comprehensive ChIP-seq analysis to map the SMARCD3-dependent epigenome we showed that Smarcd3 inhibition drives global losses in histone acetylation and BAF binding at active enhancers co-bound by FOXA1. Integrating this with RNA-seq analysis, we found that SMARCD3-BAF regulated a network of genes implicated in diverse programs converging on lipid homeostasis. Specifically, Smarcd3 deletion in vivo inhibited fatty acid metabolism, which is known to be enriched within therapy-resistant cancer cells. These data collectively identify SMARCD3 as a critical dependency in PDAC and link SWI/SNF with the epigenetic control of cell state and metabolism in PDAC.

2022-11-18 | MSV000090744 | MassIVE

Molecular subtypes in pancreatic adenocarcinoma [pancreatic cancer cell lines]

Project description:The goal of the study was to examine the transcriptional profile of pancreatic cancer cell lines and assess if the molecular subtypes observed in tumor samples were represented in existing cell line models. Cell line models allow us to investigate if the molecular subtype observed in tumor have unique sensitivity profiles to anticancer drugs. 29 pancreatic cancer cell lines were compared to a mixed reference pool of 30 pancreatic cancer cell lines to identify cell line specific gene expression.

2016-06-01 | E-GEOD-77850 | biostudies-arrayexpress

Ikarugamycin blocks the glycolysis in pancreatic cancer

Project description:Ikarugamycin blocks the glycolysis in pancreatic cancer

| PRJNA494233 | ENA

Pancreatic Cancer HPAF/CD18 cells: Ecd knockdown vs Scrambled

Project description:Purpose: To study the expression and function of a novel cell cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer (PC) pathogenesis. Experimental Design: Immunohistochemical expression profiling of Ecd was done in non-neoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in PC progression, Ecd was stably knocked down in PC cell line followed by in vitro and in vivo functional assays. Results: Normal pancreatic ducts show very weak to no Ecd expression compared to significant positive expression in PC tissues (mean±SE composite score: 0.3±0.2 and 3.8±0.2 respectively, p<0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1 to PanIN-3). Analysis of matched primary tumors and metastases from PC patients revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Further, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of PC cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in PC cells and was subsequently shown to modulate glucose uptake, lactate production and ATP generation by PC cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells. Conclusion: Ecd is a novel tumor promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells. Two-condition experiment, Ecd knockdown vs Scrambled cells. Biological replicates: 3 Ecd knockdownl, 3 Scrambled, independently grown and harvested. One replicate per array

2012-08-09 | E-GEOD-39988 | biostudies-arrayexpress

Differential expression of metabolic genes in tumor and stromal components in primary and metastatic loci in pancreatic adenocarcinomas

2012-04-29 | GSE34153 | GEO

Expression data from human pancreatic tissue from healthy subjects and pancreatic ductal adenocarcinoma patients

Project description:CEL mutation carriers may have increased pancreatic cancer risk. We used microarrays to detail the global programme of gene expression underlying pancreatic cancer progression in a CEL mutation carrier and non-CEL mutation pancreatic cancer patients + controls.

2017-06-20 | GSE46234 | GEO

Breast Cancer Stem Cells Regulated Metabolism Remodeling of Bulk Tumor Cells Drives Immune Evasion

Project description:Reprogramming of energy metabolism plays pivotal roles in cancer progression and immune surveillance. Here, we demonstrated that breast cancer cells showed positive feedback enhanced aerobic glycolysis in hypoxia condition. Further investigation suggested that breast cancer stem cells (BCSCs) induced by hypoxia stimulate aerobic glycolysis in bulk tumor cells. Cells cultured with hypoxic tumor cell- or BCSC-secretome exhibited similar gene expression patterns, with global remodeling of metabolism pathways, particularly glycolysis. BCSCs regulated glycolysis promoted breast cancer progression and evasion of immune surveillance. Screening of BCSC secretome identified MIF as a pivotal factor that potentiated glycolysis by increasing the expression of ALDOC. Breast cancer cell–intrinsic MIF depletion inhibited tumor progression and augmented intratumoral cytolytic CD8+ T cells and pro-inflammatory macrophages. Targeting MIF optimized immune checkpoint therapy of breast cancer in both syngeneic mouse models and humanized mouse model. Hence, this study delineates the contribution of BCSC regulated bulk tumor cell glycolysis in immune surveillance; and thereby proposes strategies to optimize immunotherapy in breast cancer.

2023-06-06 | GSE220616 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data