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World Journal of Gastroenterology Aug 2016Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC.
Topics: Acinar Cells; Adaptor Proteins, Signal Transducing; Carcinoma, Pancreatic Ductal; Cellular Reprogramming; Chemokines; Humans; Intercellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Metaplasia; NFATC Transcription Factors; Pancreatic Neoplasms; SOX9 Transcription Factor; TRPP Cation Channels; Wnt Signaling Pathway
PubMed: 27610015
DOI: 10.3748/wjg.v22.i31.7046 -
Cell Stem Cell Aug 2023In this issue, Jiang and colleagues employ multiple lineage-tracing approaches to elaborate on the role of Tff2+ transit-amplifying progenitor cells in the pancreatic...
In this issue, Jiang and colleagues employ multiple lineage-tracing approaches to elaborate on the role of Tff2+ transit-amplifying progenitor cells in the pancreatic acinar compartment of mice. This work provides insights into the steady-state homeostasis and tumor-suppressive features of certain progenitor cells and presents findings on acinar cell heterogeneity.
Topics: Mice; Animals; Acinar Cells; Pancreas; Pancreatic Neoplasms; Carcinogenesis; Homeostasis
PubMed: 37541205
DOI: 10.1016/j.stem.2023.07.008 -
Seminars in Diagnostic Pathology Sep 2016Our understanding about the family of acinar neoplasms of the pancreas has grown substantially over the past 25 years. The prototype is acinar cell carcinoma, an... (Review)
Review
Our understanding about the family of acinar neoplasms of the pancreas has grown substantially over the past 25 years. The prototype is acinar cell carcinoma, an uncommon variant of pancreatic carcinoma that demonstrates production of pancreatic exocrine enzymes, verifiable using immunohistochemistry, and exhibits characteristic histologic features. Related neoplasms include mixed acinar carcinomas such as mixed acinar neuroendocrine carcinoma and mixed acinar ductal carcinoma. In the pediatric age group, pancreatoblastoma is also closely related. Cystic and extrapancreatic forms have been described. These neoplasms share molecular alterations that are distinct from the more common ductal and neuroendocrine neoplasms of the pancreas. Although there is a broad range of genetic findings, a number of potential therapeutic targets have emerged. This review explores the clinical and pathologic features of pancreatic acinar neoplasms along with their more common molecular phenotypes. The differential diagnosis with other pancreatic neoplasms is explored as well.
Topics: Acinar Cells; Carcinoma, Acinar Cell; Humans; Pancreatic Neoplasms; Research
PubMed: 27320062
DOI: 10.1053/j.semdp.2016.05.009 -
Journal of Translational Medicine Apr 2024Acute pancreatitis (AP) is a clinically common acute abdominal disease, whose pathogenesis remains unclear. The severe patients usually have multiple complications and...
BACKGROUND
Acute pancreatitis (AP) is a clinically common acute abdominal disease, whose pathogenesis remains unclear. The severe patients usually have multiple complications and lack specific drugs, leading to a high mortality and poor outcome. Acinar cells are recognized as the initial site of AP. However, there are no precise single-cell transcriptomic profiles to decipher the landscape of acinar cells during AP, which are the missing pieces of jigsaw we aimed to complete in this study.
METHODS
A single-cell sequencing dataset was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in acinar cells. The pathways' activities were evaluated by gene sets enrichment analysis (GSEA) and single-cell gene sets variation analysis (GSVA). Pseudotime analysis was performed to describe the development trajectories of acinar cells. We also constructed the protein-protein interaction (PPI) network and identified the hub genes. Another independent single-cell sequencing dataset of pancreas samples from AP mice and a bulk RNA sequencing dataset of peripheral blood samples from AP patients were also analyzed.
RESULTS
In this study, we identified genetic markers of each cell type in the pancreas of AP mice based on single-cell sequencing datasets and analyzed the transcription changes in acinar cells. We found that acinar cells featured acinar-ductal metaplasia (ADM), as well as increased endocytosis and vesicle transport activity during AP. Notably, the endoplasmic reticulum stress (ERS) and ER-associated degradation (ERAD) pathways activated by accumulation of unfolded/misfolded proteins in acinar cells could be pivotal for the development of AP.
CONCLUSION
We deciphered the distinct roadmap of acinar cells in the early stage of AP at single-cell level. ERS and ERAD pathways are crucially important for acinar homeostasis and the pathogenesis of AP.
Topics: Humans; Mice; Animals; Pancreatitis; Acinar Cells; RNA-Seq; Acute Disease; Endoplasmic Reticulum Stress
PubMed: 38605381
DOI: 10.1186/s12967-024-05156-0 -
Cell Death & Disease Jul 2023Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic...
Heparanase 2 (Hpa2, HPSE2) is a close homolog of heparanase. Hpa2, however, lacks intrinsic heparan sulfate (HS)-degrading activity, the hallmark of heparanase enzymatic activity. Mutations of HPSE2 were identified in patients diagnosed with urofacial syndrome (UFS), a rare genetic disorder that exhibits abnormal facial expression and bladder voiding dysfunction, leading to renal damage and eventually renal failure. In order to reveal the role of HPSE2 in tissue homeostasis, we established a conditional Hpa2-KO mouse. Interestingly, the lack of Hpa2 was associated with a marked decrease in the expression of key pancreatic transcription factors such as PTF1, GATA6, and Mist1. This was associated with a two-fold decrease in pancreas weight, increased pancreatic inflammation, and profound morphological alterations of the pancreas. These include massive accumulation of fat cells, possibly a result of acinar-to-adipocyte transdifferentiation (AAT), as well as acinar-to-ductal metaplasia (ADM), both considered to be pro-tumorigenic. Furthermore, exposing Hpa2-KO but not wild-type mice to a carcinogen (AOM) and pancreatic inflammation (cerulein) resulted in the formation of pancreatic intraepithelial neoplasia (PanIN), lesions that are considered to be precursors of invasive ductal adenocarcinoma of the pancreas (PDAC). These results strongly support the notion that Hpa2 functions as a tumor suppressor. Moreover, Hpa2 is shown here for the first time to play a critical role in the exocrine aspect of the pancreas.
Topics: Mice; Animals; Pancreas; Acinar Cells; Pancreatic Neoplasms; Pancreatitis; Cell Differentiation; Inflammation; Carcinoma, Pancreatic Ductal
PubMed: 37491420
DOI: 10.1038/s41419-023-05990-y -
American Journal of Physiology.... Sep 2023Excessive alcohol intake is a major risk factor for pancreatitis, sensitizing the exocrine pancreas to stressors by mechanisms that remain obscure. Impaired autophagy...
Excessive alcohol intake is a major risk factor for pancreatitis, sensitizing the exocrine pancreas to stressors by mechanisms that remain obscure. Impaired autophagy drives nonalcoholic pancreatitis, but the effects of ethanol (EtOH) and alcoholic pancreatitis on autophagy are poorly understood. Here, we find that ethanol reduces autophagosome formation in pancreatic acinar cells, both in a mouse model of alcoholic pancreatitis induced by a combination of EtOH diet and cerulein (a CCK ortholog) and in EtOH+CCK-treated acinar cells (ex vivo model). Ethanol treatments decreased pancreatic level of LC3-II, a key mediator of autophagosome formation. This was caused by ethanol-induced upregulation of ATG4B, a cysteine protease that, cell dependently, regulates the balance between cytosolic LC3-I and membrane-bound LC3-II. We show that ATG4B negatively regulates LC3-II in acinar cells subjected to EtOH treatments. Ethanol raised ATG4B level by inhibiting its degradation, enhanced ATG4B enzymatic activity, and strengthened its interaction with LC3-II. We also found an increase in ATG4B and impaired autophagy in a dissimilar, nonsecretagogue model of alcoholic pancreatitis induced by EtOH plus palmitoleic acid. Adenoviral ATG4B overexpression in acinar cells greatly reduced LC3-II and inhibited autophagy. Furthermore, it aggravated trypsinogen activation and necrosis, mimicking key responses of ex vivo alcoholic pancreatitis. Conversely, shRNA Atg4B knockdown enhanced autophagosome formation and alleviated ethanol-induced acinar cell damage. The results reveal a novel mechanism, whereby ethanol inhibits autophagosome formation and thus sensitizes pancreatitis, and a key role of ATG4B in ethanol's effects on autophagy. Enhancing pancreatic autophagy, particularly by downregulating ATG4B, could be beneficial in mitigating the severity of alcoholic pancreatitis. Ethanol sensitizes mice and humans to pancreatitis, but the underlying mechanisms remain obscure. Autophagy is important for maintaining pancreatic acinar cell homeostasis, and its impairment drives pancreatitis. This study reveals a novel mechanism, whereby ethanol inhibits autophagosome formation through upregulating ATG4B, a key cysteine protease. ATG4B upregulation inhibits autophagy in acinar cells and aggravates pathological responses of experimental alcoholic pancreatitis. Enhancing pancreatic autophagy, particularly by down-regulating ATG4B, could be beneficial for treatment of alcoholic pancreatitis.
Topics: Animals; Humans; Mice; Acinar Cells; Autophagy; Autophagy-Related Proteins; Cysteine Endopeptidases; Cysteine Proteases; Ethanol; Pancreatitis, Alcoholic; Up-Regulation
PubMed: 37431575
DOI: 10.1152/ajpgi.00053.2023 -
Cell Reports Dec 2023While programmed cell death plays important roles during morphogenetic stages of development, post-differentiation organ growth is considered an efficient process...
While programmed cell death plays important roles during morphogenetic stages of development, post-differentiation organ growth is considered an efficient process whereby cell proliferation increases cell number. Here we demonstrate that early postnatal growth of the pancreas unexpectedly involves massive acinar cell elimination. Measurements of cell proliferation and death in the human pancreas in comparison to the actual increase in cell number predict daily elimination of 0.7% of cells, offsetting 88% of cell formation over the first year of life. Using mouse models, we show that death is associated with mitosis, through a failure of dividing cells to generate two viable daughters. In p53-deficient mice, acinar cell death and proliferation are reduced, while organ size is normal, suggesting that p53-dependent developmental apoptosis triggers compensatory proliferation. We propose that excess cell turnover during growth of the pancreas, and presumably other organs, facilitates robustness to perturbations and supports maintenance of tissue architecture.
Topics: Animals; Mice; Humans; Acinar Cells; Tumor Suppressor Protein p53; Pancreas; Cell Differentiation; Apoptosis
PubMed: 37995187
DOI: 10.1016/j.celrep.2023.113457 -
Cancer Discovery Mar 2021Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression...
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell-derived and acinar cell-derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution. SIGNIFICANCE: Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention..
Topics: Acinar Cells; Alleles; Animals; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Computational Biology; Disease Models, Animal; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Mice; Mutation; Oncogenes; Pancreatic Neoplasms; Prognosis; Proto-Oncogene Proteins p21(ras); Transcriptome
PubMed: 34009137
DOI: 10.1158/2159-8290.CD-20-0633 -
Biomolecules Oct 2022The cytosolic concentration of free calcium ions ([Ca2+]) is an important intracellular messenger in most cell types, and the spatial distribution of [Ca2+] is often...
The cytosolic concentration of free calcium ions ([Ca2+]) is an important intracellular messenger in most cell types, and the spatial distribution of [Ca2+] is often critical. In a salivary gland acinar cell, a polarised epithelial cell, whose principal function is to transport water and thus secrete saliva, [Ca2+] controls the secretion of primary saliva, but increases in [Ca2+] are localised to the apical regions of the cell. Hence, any quantitative explanation of how [Ca2+] controls saliva secretion must take into careful account the spatial distribution of the various Ca2+ sources, Ca2+ sinks, and Ca2+-sensitive ion channels. Based on optical slices, we have previously constructed anatomically accurate three-dimensional models of seven salivary gland acinar cells, and thus shown that a model in which Ca2+ responses are confined to the apical regions of the cell is sufficient to provide a quantitative and predictive explanation of primary saliva secretion. However, reconstruction of such anatomically accurate cells is extremely time consuming and inefficient. Here, we present an alternative, mostly automated method of constructing three-dimensional cells that are approximately anatomically accurate and show that the new construction preserves the quantitative accuracy of the model.
Topics: Calcium; Acinar Cells; Ion Channels; Ions; Water
PubMed: 36291663
DOI: 10.3390/biom12101455 -
Journal of Visualized Experiments : JoVE May 2023The pancreas includes two major systems: the endocrine system, which produces and secretes hormones, and the exocrine system, which accounts for approximately 90% of the...
The pancreas includes two major systems: the endocrine system, which produces and secretes hormones, and the exocrine system, which accounts for approximately 90% of the pancreas and includes cells that produce and secrete digestive enzymes. The digestive enzymes are produced in the pancreatic acinar cells, stored in vesicles called zymogens, and are then released into the duodenum via the pancreatic duct to initiate metabolic processes. The enzymes produced by the acinar cells can kill cells or degrade cell-free RNA. In addition, acinar cells are fragile, and common dissociation protocols result in a large number of dead cells and cell-free proteases and RNases. Therefore, one of the biggest challenges in pancreatic tissue digestion is recovering intact and viable cells, especially acinar cells. The protocol presented in this article shows a two-step method that we developed to meet this need. The protocol can be used to digest normal pancreata, pancreata that include pre-malignant lesions, or pancreatic tumors that include a large number of stromal and immune cells.
Topics: Humans; Pancreas; Acinar Cells; Pancreatic Neoplasms; Cell-Free Nucleic Acids; Dissection; Gastrointestinal Agents
PubMed: 37306453
DOI: 10.3791/64871