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Nature Communications Dec 2023Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant...
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
Topics: Animals; Mice; Cell Line, Tumor; Pancreatic Neoplasms; Pancreas; Carcinoma, Pancreatic Ductal; Fibroblasts; Carcinogenesis; Tumor Microenvironment
PubMed: 38057326
DOI: 10.1038/s41467-023-42178-6 -
Haematologica Oct 2023Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities....
Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30% of cases, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. Over the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes; these are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.
Topics: Humans; Shwachman-Diamond Syndrome; Lipomatosis; Bone Marrow Diseases; Mutation; Exocrine Pancreatic Insufficiency; Signal Recognition Particle
PubMed: 37226705
DOI: 10.3324/haematol.2023.282949 -
Journal of Experimental & Clinical... Oct 2023Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes...
BACKGROUND
Pancreatitis is known to be an important risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the exact molecular mechanisms of how inflammation promotes PDAC are still not fully understood. Regnase-1, an endoribonuclease, regulates immune responses by degrading mRNAs of inflammation-related genes. Herein, we investigated the role of Regnase-1 in PDAC.
METHODS
Clinical significance of intratumor Regnase-1 expression was evaluated by immunohistochemistry in 39 surgically-resected PDAC patients. The functional role of Regnase-1 was investigated by pancreas-specific Regnase-1 knockout mice and Kras-mutant Regnase-1 knockout mice. The mechanistic studies with gene silencing, RNA immunoprecipitation sequencing (RIP-seq) and immune cell reconstitution were performed in human/mouse PDAC cell lines and a syngeneic orthotopic tumor transplantation model of KrasG12D-mutant and Trp53-deficient PDAC cells.
RESULTS
Regnase-1 expression was negatively correlated with the clinical outcomes and an independent predictor of poor relapse-free and overall survival in PDAC patients. Pancreas-specific Regnase-1 deletion in mice promoteed pancreatic cancer with PMN-MDSC infiltration and shortened their survival. A syngeneic orthotopic PDAC model exhibited that Regnase-1 downregulation accelerated tumor progression via recruitment of intratumor CD11b MDSCs. Mechanistically, Regnase-1 directly negatively regulated a variety of chemokines/cytokines important for MDSC recruitment and activation, including CXCL1, CXCL2, CSF2, and TGFβ, in pancreatic cancer cells. We subsequently showed that IL-1β-mediated Regnase-1 downregulation recruited MDSCs to tumor sites and promoted pancreatic cancer progression via mitigation of cytotoxic T lympohocytes-mediated antitumor immunity.
CONCLUSIONS
IL-1b-mediated Regnase-1 downregulation induces MDSCs and promotes pancreatic cancer through the evasion of anticancer immunity.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Down-Regulation; Inflammation; Mice, Knockout; Myeloid-Derived Suppressor Cells; Pancreatic Neoplasms; Ribonucleases
PubMed: 37814340
DOI: 10.1186/s13046-023-02831-w -
International Journal of Molecular... Aug 2023The members of the cytokine interleukin 17 (IL-17) family, along with their receptors (IL-17R), are vital players in a range of inflammatory diseases and cancer.... (Review)
Review
The members of the cytokine interleukin 17 (IL-17) family, along with their receptors (IL-17R), are vital players in a range of inflammatory diseases and cancer. Although generally regarded as proinflammatory, the effects they exhibit on cancer progression are a double-edged sword, with both antitumor and protumor activities being discovered. There is growing evidence that the IL-17 signaling pathways have significant impacts on the tumor microenvironment (TME), immune response, and inflammation in various types of cancer, including pancreatic cancer. However, the detailed mechanistic functions of the IL-17/IL-17R families in pancreatic cancer were rarely systematically elucidated. This review considers the role of the IL-17/IL-17R families in inflammation and tumor immunity and elaborates on the mechanistic functions and correlations of these members with pathogenesis, progression, and chemoresistance in pancreatic cancer. By summarizing the advanced findings on the role of IL-17/IL17R family members and IL-17 signaling pathways at the molecular level, cellular level, and disease level in pancreatic cancer, this review provides an in-depth discussion on the potential of IL-17/IL-17R as prognostic markers and therapeutic targets in pancreatic cancer.
Topics: Humans; Cytokines; Inflammation; Interleukin-17; Pancreatic Neoplasms; Tumor Microenvironment
PubMed: 37686343
DOI: 10.3390/ijms241713539 -
Frontiers in Endocrinology 2023To assess the prevalence of pancreatic steatosis and iron overload in non-alcoholic fatty liver disease (NAFLD) and their correlation with liver histology severity and...
OBJECTIVE
To assess the prevalence of pancreatic steatosis and iron overload in non-alcoholic fatty liver disease (NAFLD) and their correlation with liver histology severity and the risk of cardiometabolic diseases.
METHOD
A prospective, multicenter study including NAFLD patients with biopsy and paired Magnetic Resonance Imaging (MRI) was performed. Liver biopsies were evaluated according to NASH Clinical Research Network, hepatic iron storages were scored, and digital pathology quantified the tissue proportionate areas of fat and iron. MRI-biomarkers of fat fraction (PDFF) and iron accumulation (R2*) were obtained from the liver and pancreas. Different metabolic traits were evaluated, cardiovascular disease (CVD) risk was estimated with the atherosclerotic CVD score, and the severity of iron metabolism alteration was determined by grading metabolic hiperferritinemia (MHF). Associations between CVD, histology and MRI were investigated.
RESULTS
In total, 324 patients were included. MRI-determined pancreatic iron overload and moderate-to severe steatosis were present in 45% and 25%, respectively. Liver and pancreatic MRI-biomarkers showed a weak correlation (r=0.32 for PDFF, r=0.17 for R2*). Pancreatic PDFF increased with hepatic histologic steatosis grades and NASH diagnosis (<0.001). Prevalence of pancreatic steatosis and iron overload increased with the number of metabolic traits (<0.001). Liver R2* significantly correlated with MHF (AUC=0.77 [0.72-0.82]). MRI-determined pancreatic steatosis (OR=3.15 [1.63-6.09]), and iron overload (OR=2.39 [1.32-4.37]) were independently associated with high-risk CVD. Histologic diagnosis of NASH and advanced fibrosis were also associated with high-risk CVD.
CONCLUSION
Pancreatic steatosis and iron overload could be of utility in clinical decision-making and prognostication of NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Cardiovascular Diseases; Prospective Studies; Risk Factors; Lipid Metabolism Disorders; Pancreatic Diseases; Iron Overload; Iron; Heart Disease Risk Factors
PubMed: 37600695
DOI: 10.3389/fendo.2023.1213441 -
Frontiers in Immunology 2023During development of pancreatic cancer macrophage-mediated inflammatory processes and the formation of cancerous lesions are tightly connected. Based on insight from... (Review)
Review
During development of pancreatic cancer macrophage-mediated inflammatory processes and the formation of cancerous lesions are tightly connected. Based on insight from mouse models we provide an overview on the functions of classically-activated pro-inflammatory and alternatively-activated anti-inflammatory macrophages in the initiation and progression of pancreatic cancer. We highlight their roles in earliest events of tumor initiation such as acinar-to-ductal metaplasia (ADM), organization of the fibrotic lesion microenvironment, and growth of low-grade (LG) lesions. We then discuss their roles as tumor-associated macrophages (TAM) in progression to high-grade (HG) lesions with a cancerous invasive phenotype and an immunosuppressive microenvironment. Another focus is on how targeting these macrophage populations can affect immunosuppression, fibrosis and responses to chemotherapy, and eventually how this knowledge could be used for novel therapy approaches for patients with pancreatic ductal adenocarcinoma (PDA).
Topics: Animals; Mice; Pancreatic Neoplasms; Macrophages; Carcinoma, Pancreatic Ductal; Cognition; Tumor Microenvironment
PubMed: 37638028
DOI: 10.3389/fimmu.2023.1237711 -
Frontiers in Immunology 2023The interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The interleukin-1 pathway has been linked to pancreatic diseases. We applied the Mendelian randomization approach to explore whether higher interleukin-1 receptor antagonist (IL-1RA) levels reduce the risk of acute and chronic pancreatitis and pancreatic cancer.
METHODS
Genetic variants associated with blood IL-1RA levels at the genome-wide significance level and located 5MB downstream or upstream of the gene were extracted from a genome-wide meta-analysis of 21,758 participants. After pruning, genetic variants without linkage disequilibrium were used as genetic instrument for IL-1RA. Summary-level data on acute and chronic pancreatitis and pancreatic cancer were obtained from the UK Biobank and FinnGen studies. The associations were meta-analyzed for one outcome from two sources.
RESULTS
Genetically predicted higher levels of IL-1RA were associated with a lower risk of acute and chronic pancreatitis and pancreatic cancer. In the meta-analysis of UK Biobank and FinnGen, the combined odds ratio was 0.87 (95% confidence interval [CI] 0.77-0.97, =0.003) for acute pancreatitis, 0.73 (95% CI 0.65-0.82, =2.93×10) for chronic pancreatitis, and 0.86 (95% CI 0.77-0.96, =0.009) for pancreatic cancer per one standard deviation increment in genetically predicted levels of IL-1RA.
CONCLUSION
This study suggests a protective role of IL-1RA in three major pancreatic diseases, which hints the therapeutic potentials of IL-1RA in pancreatic diseases.
Topics: Humans; Interleukin 1 Receptor Antagonist Protein; Acute Disease; Mendelian Randomization Analysis; Receptors, Interleukin-1; Pancreatitis, Chronic; Pancreatic Neoplasms
PubMed: 37781392
DOI: 10.3389/fimmu.2023.1240754 -
Frontiers in Immunology 2023Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease mainly affecting the rectum and colon and causing diarrhoea and mucopurulent stools. UC can present... (Review)
Review
Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease mainly affecting the rectum and colon and causing diarrhoea and mucopurulent stools. UC can present with extraintestinal manifestations in various organs and systems and can be associated with various comorbidities. Autoimmune pancreatitis (AIP) is a specific type of pancreatitis associated with autoimmune abnormalities and is divided into two clinical types: type 1 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (idiopathic ductocentric pancreatitis). The current study shows an association between type 2 AIP and UC, which may be related to genetic susceptibility, inflammatory factors, and immune response. The most common manifestation of AIP in patients with type 2 AIP-UC is abdominal pain with elevated pancreatic enzymes, whereas the presentation of UC in type 2 AIP-UC is more severe, with an increased risk of UC-related surgery. This review focuses on diagnosis, prevalence, pathogenesis, impact, and treatment to better understand type 2 AIP-UC, explore the molecular mechanisms of this condition, and encourage further research into the management of type 2 AIP-UC.
Topics: Humans; Colitis, Ulcerative; Autoimmune Pancreatitis; Retrospective Studies; Autoimmune Diseases; Pancreatitis
PubMed: 38124742
DOI: 10.3389/fimmu.2023.1288390 -
Biomolecules Feb 2024Recent studies have shown that a pro-inflammatory diet and dysbiosis, especially a high level of trimethylamine-N-oxide (TMAO), are associated with various adverse... (Review)
Review
Recent studies have shown that a pro-inflammatory diet and dysbiosis, especially a high level of trimethylamine-N-oxide (TMAO), are associated with various adverse health conditions. Cardiovascular diseases and pancreatic diseases are two major morbidities in the modern world. Through this narrative review, we aimed to summarize the association between a pro-inflammatory diet, gut microbiota, and cardiovascular and pancreatic diseases, along with their underlying mechanisms. Our review revealed that TMAO is associated with the development of cardiovascular diseases by promoting platelet aggregation, atherosclerotic plaque formation, and vascular inflammation. TMAO is also associated with the development of acute pancreatitis. The pro-inflammatory diet is associated with an increased risk of pancreatic cancer and cardiovascular diseases through mechanisms that include increasing TMAO levels, activating the lipopolysaccharides cascade, and the direct pro-inflammatory effect of certain nutrients. Meanwhile, an anti-inflammatory diet decreases the risk of cardiovascular diseases and pancreatic cancer.
Topics: Humans; Gastrointestinal Microbiome; Cardiovascular Diseases; Acute Disease; Pancreatitis; Methylamines; Pancreatic Neoplasms
PubMed: 38397447
DOI: 10.3390/biom14020210 -
United European Gastroenterology Journal Nov 2023Chronic Pancreatitis (CP) causes morphological changes in the pancreatic tissue, leading to complications and pain, which may require endoscopic interventions.
BACKGROUND
Chronic Pancreatitis (CP) causes morphological changes in the pancreatic tissue, leading to complications and pain, which may require endoscopic interventions.
OBJECTIVE
Our aim was to determine the frequency of endoscopic procedures (EP) in CP patients and to analyse pain and quality of life (QoL) in these patients after their EP.
METHODS
This study included 1327 CP patients from the Scandinavian Baltic Pancreatic Club (SBPC) database including four countries and eight centres. We analysed patients undergoing EPs and gathered information on the EP, pancreatic function, pain, disease and duration. The EORTC C-30 QoL questionnaire was gathered prospectively and multivariable analysis was conducted on independent parameters between the groups. The reference population had no interventions (n = 870).
RESULTS
260 CP patients (22%) underwent EPs, median one year (range 0-39 years) after CP diagnosis. 68% were males. The median age was 59 (20-90) years. Most common aetiological factors were alcohol in 65% and smoking in 71%. Extracorporeal shock wave lithotripsy (ESWL) was used in 6% of the CP population and in 21% of the EP group. Biliary duct stenting was performed on 37% and pancreatic stenting was performed on 56% of the patients. There was no difference in pain patterns between patients who had pancreatic stenting and the reference population. The EP group had slightly better QoL (p = 0.047), functioning and fewer symptoms than the reference population, in the multivariable analysis there was no interaction effect analysis between the groups. The pancreatic stent group had better QoL and the same amount of pain than the reference group. The patients who needed later surgery (23%) had more pain (p = 0.043) and fatigue (p = 0.021).
CONCLUSIONS
One in five of the CP patients underwent EP. These patients scored higher on QoL responses and had better symptom scores. CP patients who had pancreatic stenting performed had the same pain patterns as the reference population. Randomised prospective trials are needed to determine the effect of endoscopy procedures on CP patients.
Topics: Male; Humans; Middle Aged; Female; Quality of Life; Prospective Studies; Pancreatic Ducts; Pancreatitis, Chronic; Endoscopy; Pain
PubMed: 37812591
DOI: 10.1002/ueg2.12466