Nr5a2heterozygosity sensitises to, and cooperates with, inflammation inKRasG12V-driven pancreatic tumourigenesis

Flández, Marta; Cendrowski, Jaroslaw; Cañamero, Marta; Salas, Antonio; Pozo, Natalia del; Schoonjans, Kristina; Real, Francisco X.

doi:10.1136/gutjnl-2012-304381

Cited by 85 publications

(108 citation statements)

References 39 publications

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“…We show that constitutive loss of one Nr5a2 allele in mice leads to a pre-inflammatory state that primes tissue for severe damage upon induction of a mild pancreatitis and delays recovery, possibly contributing to accelerated tumor progression 9 . This preinflammatory state is mediated by c-Jun overexpression and phosphorylation, a wellestablished mechanism of AP-1 activation 16 .…”

Section: Discussionmentioning

confidence: 89%

“…The cooperation between germline Nr5a2 haploinsufficiency, a somatic oncogenic mutation, and pancreatic inflammation to promote pancreatic cancer suggested the existence of functional interactions relevant to human PDAC 9 . We therefore analyzed the relationship between NR5A2 expression and pancreatitis in patients with PDAC.…”

Section: Nr5a2 Expression Pdac Risk Variants At Chr1q321 and Pancrmentioning

confidence: 99%

“…Moreover, expression of Ptf1a, a master regulator of pancreatic development and differentiation, and its target Cpa was similar in Nr5a2 wild type and heterozygous mice (Extended Data Figure 2A,B). We hypothesized that a subtle defect might exist in basal conditions because Nr5a2 +/-mice recovered poorly from a mild acute pancreatitis 9 and used RNA-Seq to compare the transcriptome of pancreata from 8-10 week old Nr5a2 +/+ and Nr5a2 +/-mice.…”

Section: Low Nr5a2 Expression In Normal Pancreas Is Associated With Amentioning

confidence: 99%

“…In mice, Nr5a2 deletion leads to variable degrees of pancreatic hypoplasia depending on the timing of its inactivation 6,8 . By contrast, constitutive Nr5a2 heterozygosity allows normal pancreatic development but is associated with impaired regeneration upon induction of mild acute inflammation and sensitizes pancreatic epithelial cells to mutant KRas-driven preneoplastic lesions and pancreatic ductal adenocarcinoma (PDAC) 9 . In humans, single nucleotide polymorphisms (SNPs) in the vicinity of NR5A2 have been associated with PDAC risk through genome wide association studies (GWAS) 10,11 .…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Cobo

Martinelli

Flández

et al. 2017

Preprint

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Tissue-specific differentiation and inflammatory programmes are thought to independently contribute to disease. The orphan nuclear receptor NR5A2 is a key regulator of pancreas differentiation and SNPs in or near the human gene are associated with risk of pancreatic cancer. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration, and cooperates with mutant KRas in tumor progression. Through global transcriptomic analysis, we uncover a basal preinflammatory state in the pancreas of Nr5a2 heterozygous mice that is reminiscent of pancreatitis-induced inflammation and is conserved in histologically normal human pancreata with reduced NR5A2 mRNA expression. In Nr5a2 +/-mice, Nr5a2 undergoes a dramatic transcriptional switch relocating from tissue-specific to inflammatory loci thereby promoting AP-1-dependent gene transcription. Importantly, deletion of c-Jun in the pancreas of these mice rescues the pre-inflammatory phenotype and the defective regenerative response to damage. These findings provide compelling evidence that the same transcriptional networks supporting homeostasis in normal tissue can be subverted to foster inflammation upon genetic or environmental constraints.

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Section: Discussionmentioning

confidence: 89%

Section: Nr5a2 Expression Pdac Risk Variants At Chr1q321 and Pancrmentioning

confidence: 99%

Section: Low Nr5a2 Expression In Normal Pancreas Is Associated With Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Cobo

Martinelli

Flández

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Common variants of these genes have also been associated with risk of obesity (81) and type II diabetes (40,91) or fasting glucose level (60). On the other hand, emerging evidence suggest that these genes also act as an oncogene or tumor suppressor gene in pancreatic carcinogenesis (8,25,41,92). It is conceivable that genes involved in organ development and differentiation may contribute to the ability of tumor cells to proliferate and evade cell death as well as reprogram progenitor cells to a state that give rise to a tumor (64).…”

Section: Genetic Factorsmentioning

confidence: 99%

Diabetes as a Risk Factor of Pancreatic Cancer

Mao

The Pancreapedia: Exocrine Pancreas Knowledge Base

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Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment

et al. 2018

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Pancreatic acinar cells synthesize, package, and secrete digestive enzymes into the duodenum to aid in nutrient absorption and meet metabolic demands. When exposed to cellular stresses and insults, acinar cells undergo a dedifferentiation process termed acinar–ductal metaplasia (ADM). ADM lesions with oncogenic mutations eventually give rise to pancreatic ductal adenocarcinoma (PDAC). In healthy pancreata, the basic helix‐loop‐helix (bHLH) factors MIST1 and PTF1a coordinate an acinar‐specific transcription network that maintains the highly developed differentiation status of the cells, protecting the pancreas from undergoing a transformative process. However, when MIST1 and PTF1a gene expression is silenced, cells are more prone to progress to PDAC. In this study, we tested whether induced MIST1 or PTF1a expression in PDAC cells could (i) re‐establish the transcriptional program of differentiated acinar cells and (ii) simultaneously reduce tumor cell properties. As predicted, PTF1a induced gene expression of digestive enzymes and acinar‐specific transcription factors, while MIST1 induced gene expression of vesicle trafficking molecules as well as activation of unfolded protein response components, all of which are essential to handle the high protein production load that is characteristic of acinar cells. Importantly, induction of PTF1a in PDAC also influenced cancer‐associated properties, leading to a decrease in cell proliferation, cancer stem cell numbers, and repression of key ATP‐binding cassette efflux transporters resulting in heightened sensitivity to gemcitabine. Thus, activation of pancreatic bHLH transcription factors rescues the acinar gene program and decreases tumorigenic properties in pancreatic cancer cells, offering unique opportunities to develop novel therapeutic intervention strategies for this deadly disease.

show abstract

Nr5a2heterozygosity sensitises to, and cooperates with, inflammation inKRas^G12V-driven pancreatic tumourigenesis

Cited by 85 publications

References 39 publications

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Diabetes as a Risk Factor of Pancreatic Cancer

Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment

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