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Genes & Development May 2006Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer's cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment.
Topics: Animals; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Humans; Mice; Mice, Mutant Strains; Pancreas; Pancreatic Neoplasms
PubMed: 16702400
DOI: 10.1101/gad.1415606 -
Science (New York, N.Y.) Sep 2021Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor...
Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report 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, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.
Topics: Acinar Cells; Animals; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Cells, Cultured; Cellular Reprogramming; Chromatin; Early Growth Response Protein 1; Enzyme Precursors; Epigenesis, Genetic; Epithelial Cells; Female; Genes, ras; MAP Kinase Signaling System; Male; Metaplasia; Mice; Mutation; Pancreas; Pancreatitis; Spheroids, Cellular; Transcriptome
PubMed: 34529467
DOI: 10.1126/science.abj0486 -
Cancer Discovery Jul 2023Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported...
UNLABELLED
Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatitis and PDAC is not well understood. Here, we report that the splicing factor SRSF1 is highly expressed in pancreatitis, PDAC precursor lesions, and tumors. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC. Mechanistically, SRSF1 activates MAPK signaling-partly by upregulating interleukin 1 receptor type 1 (IL1R1) through alternative-splicing-regulated mRNA stability. Additionally, SRSF1 protein is destabilized through a negative feedback mechanism in phenotypically normal epithelial cells expressing KRASG12D in mouse pancreas and in pancreas organoids acutely expressing KRASG12D, buffering MAPK signaling and maintaining pancreas cell homeostasis. This negative feedback regulation of SRSF1 is overcome by hyperactive MYC, facilitating PDAC tumorigenesis. Our findings implicate SRSF1 in the etiology of pancreatitis and PDAC, and point to SRSF1-misregulated alternative splicing as a potential therapeutic target.
SIGNIFICANCE
We describe the regulation of splicing factor SRSF1 expression in the context of pancreas cell identity, plasticity, and inflammation. SRSF1 protein downregulation is involved in a negative feedback cellular response to KRASG12D expression, contributing to pancreas cell homeostasis. Conversely, upregulated SRSF1 promotes pancreatitis and accelerates KRASG12D-mediated tumorigenesis through enhanced IL1 and MAPK signaling. This article is highlighted in the In This Issue feature, p. 1501.
Topics: Animals; Mice; Alternative Splicing; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Inflammation; Pancreatic Neoplasms; Pancreatitis; RNA Splicing Factors; Serine-Arginine Splicing Factors; Humans
PubMed: 37098965
DOI: 10.1158/2159-8290.CD-22-1013 -
Cancer Imaging : the Official... Jul 2020Various inflammatory abnormalities of the pancreas can mimic pancreatic ductal adenocarcinoma (PDAC) at cross-sectional imaging. Misdiagnosis of PDAC at imaging may lead... (Comparative Study)
Comparative Study Review
Various inflammatory abnormalities of the pancreas can mimic pancreatic ductal adenocarcinoma (PDAC) at cross-sectional imaging. Misdiagnosis of PDAC at imaging may lead to unnecessary surgery. On the other hand, chronic pancreatitis (CP) bears a greater risk of developing PDAC during the course of the disease. Thus, differentiation between mass-forming chronic pancreatitis (MFCP) and PDAC is important to avoid unnecessary surgery and not to delay surgery of synchronous PDAC in CP.Imaging features such as the morphology of the mass including displacement of calcifications, presence of duct penetrating, sign appearance of duct stricturing, presence or absence of vessel encasement, apparent diffusion coefficient (ADC) value and intravoxel incoherent motion (IVIM) at diffusion-weighted imaging (DWI), fluorodeoxyglucose (FDG) uptake in PET/CT, and mass perfusion parameters can help to differentiate between PDAC and MFCP. Correct interpretation of imaging features can appropriately guide biopsy and surgery, if necessary. This review summarizes the relevant computed tomography (CT) and magnetic resonance imaging (MRI) features that can help the radiologist to come to a confident diagnosis and to guide further management in equivocal cases.
Topics: Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Pancreatic Neoplasms; Pancreatitis; Tomography, X-Ray Computed
PubMed: 32703312
DOI: 10.1186/s40644-020-00324-z -
Cellular and Molecular Life Sciences :... Jul 2023Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of... (Review)
Review
Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-β, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.
Topics: Mice; Animals; Pancreatic Neoplasms; Pancreatitis; Pancreas; Acinar Cells; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37452870
DOI: 10.1007/s00018-023-04855-z -
Cell Stem Cell Jun 2021The exocrine pancreas, consisting of ducts and acini, is the site of origin of pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Our understanding of the genesis...
The exocrine pancreas, consisting of ducts and acini, is the site of origin of pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Our understanding of the genesis and progression of human pancreatic diseases, including PDAC, is limited because of challenges in maintaining human acinar and ductal cells in culture. Here we report induction of human pluripotent stem cells toward pancreatic ductal and acinar organoids that recapitulate properties of the neonatal exocrine pancreas. Expression of the PDAC-associated oncogene GNAS induces cystic growth more effectively in ductal than acinar organoids, whereas KRAS is more effective in modeling cancer in vivo when expressed in acinar compared with ductal organoids. KRAS, but not GNAS, induces acinar-to-ductal metaplasia-like changes in culture and in vivo. We develop a renewable source of ductal and acinar organoids for modeling exocrine development and diseases and demonstrate lineage tropism and plasticity for oncogene action in the human pancreas.
Topics: Acinar Cells; Carcinoma, Pancreatic Ductal; Humans; Infant, Newborn; Oncogenes; Organoids; Pancreas; Pancreas, Exocrine; Pancreatic Neoplasms; Stem Cells
PubMed: 33915081
DOI: 10.1016/j.stem.2021.03.022 -
Gastroenterology Jan 2022Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human...
BACKGROUND & AIMS
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human PDACs and are sufficient to promote acinar-to-ductal metaplasia (ADM) during tumor initiation. The roles of miRNAs in oncogenic Kras-induced ADM are incompletely understood.
METHODS
The Ptf1aLSL-Kras and Ptf1aLSL-KrasLSL-p53R172H/ and caerulein-induced acute pancreatitis mice models were used. mir-802 was conditionally ablated in acinar cells to study the function of miR-802 in ADM.
RESULTS
We show that miR-802 is a highly abundant and acinar-enriched pancreatic miRNA that is silenced during early stages of injury or oncogenic Kras-induced transformation. Genetic ablation of mir-802 cooperates with Kras by promoting ADM formation. miR-802 deficiency results in de-repression of the miR-802 targets Arhgef12, RhoA, and Sdc4, activation of RhoA, and induction of the downstream RhoA effectors ROCK1, LIMK1, COFILIN1, and EZRIN, thereby increasing F-actin rearrangement. mir-802 ablation also activates SOX9, resulting in augmented levels of ductal and attenuated expression of acinar identity genes. Consistently with these findings, we show that this miR-802-RhoA-F-actin network is activated in biopsies of pancreatic cancer patients and correlates with poor survival.
CONCLUSIONS
We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming, and PDAC initiation. Modulation of the miR-802-RhoA-F-actin network may be a new strategy to interfere with pancreatic carcinogenesis.
Topics: Acinar Cells; Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cellular Reprogramming; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Transgenic; MicroRNAs; Mutation; Pancreas; Pancreatic Neoplasms; Pancreatitis; Proto-Oncogene Proteins p21(ras); SOX9 Transcription Factor; Signal Transduction
PubMed: 34547282
DOI: 10.1053/j.gastro.2021.09.029 -
Surgical Pathology Clinics Dec 2016Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is... (Review)
Review
Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is multifactorial and involves complex interaction of environmental, genetic, and/or other risk factors. The pathology is dependent on the underlying pathogenesis of the disease. This review describes the clinical, gross, and microscopic findings of the main subtypes of chronic pancreatitis: alcoholic chronic pancreatitis, obstructive chronic pancreatitis, paraduodenal ("groove") pancreatitis, pancreatic divisum, autoimmune pancreatitis, and genetic factors associated with chronic pancreatitis. As pancreatic ductal adenocarcinoma may be confused with chronic pancreatitis, the main distinguishing features between these 2 diseases are discussed.
Topics: Alcohol-Induced Disorders; Autoimmune Diseases; Carcinoma, Pancreatic Ductal; Chronic Disease; Diagnosis, Differential; Humans; Pancreas; Pancreatic Ducts; Pancreatic Pseudocyst; Pancreatitis
PubMed: 27926364
DOI: 10.1016/j.path.2016.05.008 -
Nature Communications Dec 2020Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion...
Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion of Gpx4, an antioxidant enzyme reported as an important ferroptosis suppressor, in the pancreas of mice with cerulean- or L-arginine-induced pancreatitis, and in an oncogenic Kras murine model of spontaneous pancreatic ductal adenocarcinoma (PDAC). We find that either high-iron diets or Gpx4 depletion promotes 8-OHG release and thus activates the TMEM173/STING-dependent DNA sensor pathway, which results in macrophage infiltration and activation during Kras-driven PDAC in mice. Consequently, the administration of liproxstatin-1 (a ferroptosis inhibitor), clophosome-mediated macrophage depletion, or pharmacological and genetic inhibition of the 8-OHG-TMEM173 pathway suppresses Kras-driven pancreatic tumorigenesis in mice. GPX4 is also a prognostic marker in patients with PDAC. These findings provide pathological and mechanistic insights into ferroptotic damage in PDAC tumorigenesis in mice.
Topics: Animals; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Death; Cell Transformation, Neoplastic; DNA; Diet; Disease Models, Animal; Female; Ferroptosis; Humans; Iron; Macrophages; Male; Membrane Proteins; Mice; Mice, Knockout; Pancreas; Pancreatitis; Phospholipid Hydroperoxide Glutathione Peroxidase; Proto-Oncogene Proteins p21(ras); Quinoxalines; Spiro Compounds; Tumor Microenvironment
PubMed: 33311482
DOI: 10.1038/s41467-020-20154-8 -
Proceedings of the National Academy of... Sep 2019Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse...
Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.
Topics: Adult; Animals; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Disease Progression; Extracellular Matrix; Female; Humans; Male; Mice; Mice, Inbred C57BL; Pancreas; Pancreatic Neoplasms; Pancreatitis, Chronic; Proteomics; Stromal Cells; Xenograft Model Antitumor Assays
PubMed: 31484774
DOI: 10.1073/pnas.1908626116