Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation

ABSTRACT: Oncogenic mutations in Kras initiate neoplastic transformation in the pancreas through a process that hijacks the activity of developmental regulators and induces an inflammatory microenvironment. We report that the homeodomain transcription factor Prox1 is a novel component of a progenitor signature that is activated in acinar cells undergoing dedifferentiation and ductal metaplasia conversion. Also, the conditional deletion of a single Prox1 allele markedly accelerates early transformation and significantly enhances features of inflammation in pancreatic tissues carrying a Kras oncogene. By using in vitro and in silico approaches, we demonstrate that Prox1 negatively regulates the expression of proinflammatory genes and genes implicated in malignant transformation in pancreatic cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE64319 | GEO | 2016/05/09

SECONDARY ACCESSION(S): PRJNA270747

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation

Project description:Oncogenic mutations in Kras initiate neoplastic transformation in the pancreas through a process that hijacks the activity of developmental regulators and induces an inflammatory microenvironment. We report that the homeodomain transcription factor Prox1 is a novel component of a progenitor signature that is activated in acinar cells undergoing dedifferentiation and ductal metaplasia conversion. Also, the conditional deletion of a single Prox1 allele markedly accelerates early transformation and significantly enhances features of inflammation in pancreatic tissues carrying a Kras oncogene. By using in vitro and in silico approaches, we demonstrate that Prox1 negatively regulates the expression of proinflammatory genes and genes implicated in malignant transformation in pancreatic cells. Microrrays were used to identify gene expression profiles and pathways that are differentially activated after enforced expression of PROX1 in the PROX1-negative human pancreatic ductal adenocarcinoma (PDAC) cell line Capan1. MSCV retroviral transduction was used to generate Capan1 cells that ectopically express PROX1 and selected for puromycin resistance. Three independent transductions with control virus (MSCV_puro) and 3 independent transductions with Prox1-cDNA virus (MSCV_PROX1_puro) were conducted for these experiments.

2016-02-11 | E-GEOD-58547 | biostudies-arrayexpress

Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation

2016-02-11 | GSE58547 | GEO

Prox1 downregulation is a prerequisite for the maturation and expansion of postnatal murine beta cells

Project description:Alterations in the expression of key transcription factors can be harmful for pancreatic beta cell homeostasis and could lead to diabetes. This study uncovered that Prox1 overexpression obstructs beta cell maturation and results in severe hyperglycemia. The function of Î²-cells is key for glucose homeostasis because they supply insulin to the entire body. Genetic or metabolic conditions that disrupt the complex physiology of Î²-cells can lead to diabetes mellitus, a prevalent life-threatening disease. Here we investigated whether sustained Prox1 expression is incompatible with Î²-cell development using a transgenic mouse approach, and report that Î²-cell maturation is drastically impaired in the presence of high levels of Prox1. We used microarrays to identify gene expression profiles and pathways that are differentially activated when Prox1 is overexpressed in murine pancreatic beta cells.

2016-02-11 | E-GEOD-68133 | biostudies-arrayexpress

Gene expression analysis of mouse pancreas carrying Prox1 ectopic acinar expression

Project description:RNA sequencing was used to identify gene expression changes in pancreatic acinar cells with ectopic expression of the homeodomain transcription factor Prox1

2022-06-01 | GSE178174 | GEO

PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (ATAC-Seq)

Project description:Tumor cell metabolic plasticity is essential for tumor progression and therapeutic response, but the mechanism for regulation of metabolic plasticity remain poorly explored. Here, we identify PROX1 as an essential determinant for tumor metabolic plasticity. Notably, PROX1 is significantly reduced in response to metabolic stress or AMPK activation and is elevated in LKB1-deficient tumors in mice and human. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK significantly alters its protein activity and allows a rapid recruitment of CUL4-DDB1 E3 ubiquitin ligase to promote PROX1 degradation under glucose starvation, a critical event that drives BCAA metabolism rewiring to suppress mTOR signaling. Importantly, PROX1 loss or Ser79 phosphorylation in HCC shows therapeutic resistance to metformin. Consistently, genetic ablation of PROX1 renders LKB1‐deficient KRAS-driven lung cancer resistant to phenformin treatment. Conversely, mice harboring non-phosphorylated PROX1 mutant or LKB1 mutant exhibit high PROX1 stabilization, promoting liver and lung cancer progression. Clinically, AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that the deficiency in the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling, and facilitating tumorigenesis and aggressiveness.

2022-09-27 | GSE214193 | GEO

PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (RNA-Seq)

2022-09-27 | GSE214192 | GEO

Comparison of Prox1 expressing and Prox1 knockout intestinal tumors and the effect of A2V+CD40

Project description:Control or A2V+CD40 treated Prox1-proficient (AP) and Prox1-deficient (APP) tumors

2020-02-04 | GSE124716 | GEO

Epithelial memory of resolved inflammation limits tissue damage while promoting pancreatic tumorigenesis [ChIP-seq]

Project description:Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, mutations of KRAS accelerate tumor development. We discovered that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, epithelial cells of the pancreas display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the prompt reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thus efficiently limiting tissue damage via rapid decrease of zymogen production. We propose that since activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.

2021-09-17 | GSE180199 | GEO

Epithelial memory of resolved inflammation limits tissue damage while promoting pancreatic tumorigenesis [scRNA-Seq]

2021-09-17 | GSE181276 | GEO

Epithelial memory of resolved inflammation limits tissue damage while promoting pancreatic tumorigenesis [RNA-seq]

2021-09-17 | GSE180211 | GEO