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Biochimica Et Biophysica Acta. Reviews... Mar 2022Pancreatic ductal metaplasia (PDM) is the transformation of potentially many type of cells in pancreas into ductal or ductal-like cells, which eventually replace the... (Review)
Review
Pancreatic ductal metaplasia (PDM) is the transformation of potentially many type of cells in pancreas into ductal or ductal-like cells, which eventually replace the existing differentiated somatic cell type(s). PDM is usually triggered by and manifests its ability to adapt to environmental and cellular stimuli and stresses. Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas. The cellular heterogeneity of PDM informs the differences in cellular origin, triggering events, functional subpopulations and evolution pathways of PDM. Currently it remains uncertain what are the exact cellular origins and functional significance of PDM, and how this process is regulated at cellular and molecular levels. The development of PDM to atypical hyperplasia is an important risk factor for pancreatic precursors, including intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Otherwise, the cellular plasticity in PDM contribute to the regeneration of both exocrine and endocrine components of pancreas. This Review will systematically describe current knowledge on the understanding of PDM biology with an emphasis on its underlying mechanisms and implications in pancreatic regeneration, inflammation and tumorigenesis.
Topics: Acinar Cells; Carcinoma, Pancreatic Ductal; Humans; Metaplasia; Pancreas; Pancreatic Neoplasms
PubMed: 35176433
DOI: 10.1016/j.bbcan.2022.188698 -
American Journal of Physiology.... Mar 2020PAK4 is the only member of the Group II p21-activated kinases (PAKs) present in rat pancreatic acinar cells and is activated by gastrointestinal...
PAK4 is the only member of the Group II p21-activated kinases (PAKs) present in rat pancreatic acinar cells and is activated by gastrointestinal hormones/neurotransmitters stimulating PLC/cAMP and by various pancreatic growth factors. However, little is known of the role of PAK4 activation in cellular signaling cascades in pancreatic acinar cells. In the present study, we examined the role of PAK4's participation in five different cholecystokinin-8 (CCK-8)-stimulated signaling pathways (PI3K/Akt, MAPK, focal adhesion kinase, GSK3, and β-catenin), which mediate many of its physiological acinar-cell effects, as well as effects in pathophysiological conditions. To define PAK4's role, the effect of two different PAK4 inhibitors, PF-3758309 and LCH-7749944, was examined under experimental conditions that only inhibited PAK4 activation and not activation of the other pancreatic PAK, Group I PAK2. The inhibitors' effects on activation of these five signaling cascades by both physiological and pathophysiological concentrations of CCK, as well as by 12--tetradecanoylphobol-13-acetate (TPA), a PKC-activator, were examined. CCK/TPA activation of focal adhesion kinases(PYK2/p125) and the accompanying adapter proteins (paxillin/p130), Mek1/2, and p44/42, but not c-Raf or other MAPKs (JNK/p38), were mediated by PAK4. Activation of PI3K/Akt/p70s6K was independent of PAK4, whereas GSK3 and β-catenin stimulation was PAK4-dependent. These results, coupled with recent studies showing PAK4 is important in pancreatic fluid/electrolyte/enzyme secretion and acinar cell growth, show that PAK4 plays an important role in different cellular signaling cascades, which have been shown to mediate numerous physiological and pathophysiological processes in pancreatic acinar cells. In pancreatic acinar cells, cholecystokinin (CCK) or 12--tetradecanoylphobol-13-acetate (TPA) activation of focal adhesion kinases (p125,PYK2) and its accompanying adapter proteins, p130CAS/paxillin; Mek1/2, p44/42, GSK3, and β-catenin are mediated by PAK4. PI3K/Akt/p70s6K, c-Raf, JNK, or p38 pathways are independent of PAK4 activation.
Topics: Acinar Cells; Animals; Crk-Associated Substrate Protein; Enzyme Activation; Enzyme Activators; Extracellular Signal-Regulated MAP Kinases; Focal Adhesion Kinase 1; Focal Adhesion Kinase 2; Glycogen Synthase Kinase 3; Male; Mitogen-Activated Protein Kinase Kinases; Pancreas, Exocrine; Paxillin; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Signal Transduction; beta Catenin; p21-Activated Kinases
PubMed: 31984786
DOI: 10.1152/ajpgi.00229.2019 -
Cell Metabolism Dec 2023The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies...
The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in Kras-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.
Topics: Mice; Animals; Proto-Oncogene Proteins p21(ras); Receptor, Insulin; Diabetes Mellitus, Type 2; Pancreatic Neoplasms; Acinar Cells; Carcinoma in Situ; Inflammation; Hyperinsulinism; Metaplasia; Obesity; Insulins
PubMed: 37913768
DOI: 10.1016/j.cmet.2023.10.003 -
Advanced Science (Weinheim,... Sep 2023Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis;...
Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti-inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia-treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury-inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.
Topics: Acinar Cells; Acute Disease; Adenosine Triphosphate; Bile Acids and Salts; Cell Hypoxia; Cellular Reprogramming; Extracellular Vesicles; Membrane Potential, Mitochondrial; Mesenchymal Stem Cells; Mitochondria; Mitochondrial Permeability Transition Pore; Pancreas; Pancreatitis; Paracrine Communication; Superoxides; Umbilical Cord; Humans
PubMed: 37409821
DOI: 10.1002/advs.202207691 -
Gut Apr 2020SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether...
OBJECTIVE
SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown.
DESIGN
TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice () together with mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism.
RESULTS
SETD2 mutant/low expression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of . Moreover, ablation in pancreatic cancer cells enhanced epithelia-mesenchymal transition (EMT) through impaired epigenetic regulation of . In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis.
CONCLUSION
Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.
Topics: Acinar Cells; Animals; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Epithelial-Mesenchymal Transition; Histone-Lysine N-Methyltransferase; Metaplasia; Mice; Mice, Knockout; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 31300513
DOI: 10.1136/gutjnl-2019-318362 -
Cytokine & Growth Factor Reviews 2023Pancreatic fibrosis is caused by excessive deposition of extracellular matrixes of collagen and fibronectin in the pancreatic tissue as a result of repeated injury often... (Review)
Review
Pancreatic fibrosis is caused by excessive deposition of extracellular matrixes of collagen and fibronectin in the pancreatic tissue as a result of repeated injury often seen in patients with chronic pancreatic diseases. The most common causative conditions include inborn errors of metabolism, chemical toxicity and autoimmune disorders. Its pathophysiology is highly complex, including acinar cell injury, acinar stress response, duct dysfunction, pancreatic stellate cell activation, and persistent inflammatory response. However, the specific mechanism remains to be fully clarified. Although the current therapeutic strategies targeting pancreatic stellate cells show good efficacy in cell culture and animal models, they are not satisfactory in the clinic. Without effective intervention, pancreatic fibrosis can promote the transformation from pancreatitis to pancreatic cancer, one of the most lethal malignancies. In the normal pancreas, the acinar component accounts for 82% of the exocrine tissue. Abnormal acinar cells may activate pancreatic stellate cells directly as cellular source of fibrosis or indirectly via releasing various substances and initiate pancreatic fibrosis. A comprehensive understanding of the role of acinar cells in pancreatic fibrosis is critical for designing effective intervention strategies. In this review, we focus on the role of and mechanisms underlying pancreatic acinar injury in pancreatic fibrosis and their potential clinical significance.
Topics: Animals; Humans; Acinar Cells; Pancreas; Pancreatic Diseases; Pancreatitis; Chronic Disease; Fibrosis
PubMed: 37291030
DOI: 10.1016/j.cytogfr.2023.05.003 -
Cell Death & Disease Aug 2023Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer...
Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanisms and regulation using primary human cells and murine experimental models. Our RNAseq analysis indicates that, in both species, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system x. To decipher its role, gene silencing, pharmacological inhibition and a knock-out mouse model were used. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
Topics: Humans; Animals; Mice; Acinar Cells; Acute Disease; Ferroptosis; Pancreatitis; Reactive Oxygen Species; Glutamic Acid
PubMed: 37604805
DOI: 10.1038/s41419-023-06063-w -
Gastroenterology Jan 2022
Topics: Acinar Cells; Humans; Metaplasia; MicroRNAs; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 34662582
DOI: 10.1053/j.gastro.2021.10.011 -
International Immunopharmacology Dec 2023Recent clinical studies have shown that serum high-density lipoprotein (HDL) levels are correlated with acute pancreatitis (AP) severity. We aimed to investigate the...
BACKGROUND AND PURPOSE
Recent clinical studies have shown that serum high-density lipoprotein (HDL) levels are correlated with acute pancreatitis (AP) severity. We aimed to investigate the role of HDL in pancreatic necrosis in AP.
EXPERIMENTAL APPROACH
ApoA-I is the main constitution and function component of HDL. The roles of healthy human-derived HDL and apoA-I mimic peptide D4F were demonstrated in AP models in vivo and in vitro. Constitutive Apoa1 genetic inhibition on AP severity, especially pancreatic necrosis was assessed in both caerulein and sodium taurocholate induced mouse AP models. In addition, constitutive (Casp1) and acinar cell conditional (Pdx1Nlrp3 and Pdx1Gsdmd) mice were used to explore the effects of HDL on acinar cell pyroptosis in AP.
KEY RESULTS
Apoa1 knockout dramatically aggravated pancreatic necrosis. Human-derived HDL protected against acinar cell death in vivo and in vitro. We found that mimic peptide D4F also protected against AP very well. Constitutive Casp1 or acinar cell-conditional Nlrp3 and Gsdmd genetic inhibition could counteract the protective effects of HDL, implying HDL may exert beneficial effects on AP through inhibiting acinar cell pyroptosis.
CONCLUSION AND IMPLICATIONS
This work demonstrates the protective role of HDL and apoA-I in AP pathology, potentially driven by the inhibition of NLRP3 inflammasome signaling and acinar cell pyroptosis. Mimic peptides have promise as specific therapies for AP.
Topics: Animals; Humans; Mice; Acinar Cells; Acute Disease; Apolipoprotein A-I; Caspase 1; Ceruletide; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatitis, Acute Necrotizing; Pyroptosis
PubMed: 37890377
DOI: 10.1016/j.intimp.2023.110950 -
Cellular and Molecular Gastroenterology... 2022The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant... (Review)
Review
The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant cellular plasticity within the pancreas appears to be exploited in tumorigenesis, with metaplastic, dedifferentiation, and transdifferentiation processes central to the development of pancreatic intraepithelial neoplasia and intraductal papillary neoplasms, precursor lesions to pancreatic ductal adenocarcinoma. In the face of shifting cellular identity, the cell of origin of pancreatic cancer has been difficult to elucidate. However, with the extensive utilization of in vivo lineage-traced mouse models coupled with insights from human samples, it has emerged that the acinar cell is most efficiently able to give rise to both intraductal papillary neoplasms and pancreatic intraepithelial neoplasia but that acinar and ductal cells can undergo malignant transformation to pancreatic ductal adenocarcinoma. In this review, we discuss the cellular reprogramming that takes place in both the normal and malignant pancreas and evaluate the current state of evidence that implicate both the acinar and ductal cell as context-dependent origins of this deadly disease.
Topics: Acinar Cells; Animals; Carcinoma, Pancreatic Ductal; Cell Plasticity; Mice; Pancreas; Pancreatic Neoplasms
PubMed: 34352406
DOI: 10.1016/j.jcmgh.2021.07.014