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International Journal of Molecular... Jun 2023Adult pancreatic acinar cells show high plasticity allowing them to change in their differentiation commitment. Pancreatic acinar-to-ductal metaplasia (ADM) is a... (Review)
Review
Adult pancreatic acinar cells show high plasticity allowing them to change in their differentiation commitment. Pancreatic acinar-to-ductal metaplasia (ADM) is a cellular process in which the differentiated pancreatic acinar cells transform into duct-like cells. This process can occur as a result of cellular injury or inflammation in the pancreas. While ADM is a reversible process allowing pancreatic acinar regeneration, persistent inflammation or injury can lead to the development of pancreatic intraepithelial neoplasia (PanIN), which is a common precancerous lesion that precedes pancreatic ductal adenocarcinoma (PDAC). Several factors can contribute to the development of ADM and PanIN, including environmental factors such as obesity, chronic inflammation and genetic mutations. ADM is driven by extrinsic and intrinsic signaling. Here, we review the current knowledge on the cellular and molecular biology of ADM. Understanding the cellular and molecular mechanisms underlying ADM is critical for the development of new therapeutic strategies for pancreatitis and PDAC. Identifying the intermediate states and key molecules that regulate ADM initiation, maintenance and progression may help the development of novel preventive strategies for PDAC.
Topics: Adult; Humans; Pancreatic Neoplasms; Pancreas; Carcinoma, Pancreatic Ductal; Acinar Cells; Carcinoma in Situ; Metaplasia; Inflammation
PubMed: 37373094
DOI: 10.3390/ijms24129946 -
JAMA Oncology Sep 2022National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas: The A021501 Phase 2 Randomized Clinical Trial.
IMPORTANCE
National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear.
OBJECTIVE
To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021.
INTERVENTIONS
Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours).
MAIN OUTCOMES AND MEASURES
Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection.
RESULTS
Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively.
CONCLUSIONS AND RELEVANCE
This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02839343.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Prospective Studies
PubMed: 35834226
DOI: 10.1001/jamaoncol.2022.2319 -
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 -
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 -
Best Practice & Research. Clinical... 2022EUS-guided treatments for focal tumor lesions has been developed since 20 years using at onset of the technique mainly local and guided alcohol injection [1-4]....
EUS-guided treatments for focal tumor lesions has been developed since 20 years using at onset of the technique mainly local and guided alcohol injection [1-4]. Pancreatic tumors are the most assessed targeted lesions for EUS treatment because of their accessibility and because EUS management could be a safe alternative to surgery. More and more pancreatic tumors are discovered mainly fortuitously due to the advances in conventional imaging (abdominal ultrasound, CT, MRI) resulting in the question of surgical management of an asymptomatic pancreatic lesion ("incidentaloma") [5-8]. The lesions detected include mostly pancreatic cystic neoplasms (PCN) and neuroendocrine tumors (NET) mainly well differentiated. Clinically, NET are mostly non-functional and do not induce secretory disorders [5-8]. Once their nature is yielded by diagnostic tests like EUS-FNA, incidental nonfunctional NET currently lead to difficult management when their largest diameter is less than 2 cm [2,4,9,10]. EUS-guided treatment for pancreatic adenocarcinoma have also been developed with recent prospective observational study and randomized control study [11,12]. Thus, therapeutic surgical choices could be challenged by EUS- guided treatment [2,4,9].
Topics: Humans; Pancreatic Neoplasms; Adenocarcinoma; Pancreas; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Magnetic Resonance Imaging; Endosonography
PubMed: 36577536
DOI: 10.1016/j.bpg.2022.101817 -
BMJ (Clinical Research Ed.) Feb 2024Chronic pancreatitis results from repeated episodes of pancreatic inflammation and associated fibrosis leading to the loss of functional exocrine and endocrine... (Review)
Review
Chronic pancreatitis results from repeated episodes of pancreatic inflammation and associated fibrosis leading to the loss of functional exocrine and endocrine pancreatic function. The disease is manifested by abdominal pain, deterioration in quality of life, food maldigestion and malabsorption, diabetes, and an increased risk for pancreatic adenocarcinoma. This review summarizes the latest evidence on the diagnosis and management of chronic pancreatitis and its manifestations. In particular, this review discusses advances in understanding of the role of genetic disorders in the mechanisms of the disease and surgical options for patients refractory to medical therapy. Furthermore, clinical trials are under way to develop medical therapeutics.
Topics: Humans; Adenocarcinoma; Quality of Life; Pancreatic Neoplasms; Pancreatitis, Chronic
PubMed: 38408777
DOI: 10.1136/bmj-2023-070920 -
Journal of Magnetic Resonance Imaging :... Feb 2021MRI has played a critical role in the evaluation of patients with pancreatic pathologies, from screening of patients at high risk for pancreatic cancer to the evaluation... (Review)
Review
MRI has played a critical role in the evaluation of patients with pancreatic pathologies, from screening of patients at high risk for pancreatic cancer to the evaluation of pancreatic cysts and indeterminate pancreatic lesions. The high mortality associated with pancreatic adenocarcinomas has spurred much interest in developing effective screening tools, with MRI using magnetic resonance cholangiopancreatography (MRCP) playing a central role in the hopes of identifying cancers at earlier stages amenable to curative resection. Ongoing efforts to improve the resolution and robustness of imaging of the pancreas using MRI may thus one day reduce the mortality of this deadly disease. However, the increasing use of cross-sectional imaging has also generated a concomitant clinical conundrum: How to manage incidental pancreatic cystic lesions that are found in over a quarter of patients who undergo MRCP. Efforts to improve the specificity of MRCP for patients with pancreatic cysts and with indeterminate pancreatic masses may be achieved with continued technical advances in MRI, including diffusion-weighted and T -weighted dynamic contrast-enhanced MRI. However, developments in quantitative MRI of the pancreas remain challenging, due to the small size of the pancreas and its upper abdominal location, adjacent to bowel and below the diaphragm. Further research is needed to improve MRI of the pancreas as a clinical tool, to positively affect the lives of patients with pancreatic abnormalities. This review focuses on various MR techniques such as MRCP, quantitative imaging, and dynamic contrast-enhanced imaging and their clinical applicability in the imaging of the pancreas, with an emphasis on pancreatic malignant and premalignant lesions. Level of Evidence 5 Technical Efficacy Stage 3 J. MAGN. RESON. IMAGING 2021;53:347-359.
Topics: Adenocarcinoma; Cholangiopancreatography, Magnetic Resonance; Humans; Magnetic Resonance Imaging; Pancreas; Pancreatic Neoplasms
PubMed: 32302044
DOI: 10.1002/jmri.27148 -
Journal of Visceral Surgery Oct 2019The circumportal pancreas (CPP) is a normal though rare anatomical variant of the pancreas resulting from fusion of ventral and dorsal pancreatic buds during...
The circumportal pancreas (CPP) is a normal though rare anatomical variant of the pancreas resulting from fusion of ventral and dorsal pancreatic buds during embryogenesis. Preoperative imaging in a 69-year-old man displayed the presence of a CPP completely encasing the portal vein. For pancreatic resection, missing a CPP is associated with a higher risk of postoperative complications.
Topics: Adenocarcinoma; Aged; Humans; Magnetic Resonance Imaging; Male; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Portal Vein
PubMed: 30773440
DOI: 10.1016/j.jviscsurg.2019.02.001