scholarly journals Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1821
Author(s):  
Ujjwal Mukund Mahajan ◽  
Ahmed Alnatsha ◽  
Qi Li ◽  
Bettina Oehrle ◽  
Frank-Ulrich Weiss ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Enrichment Analysis ◽  
Response Prediction ◽  
Ductal Adenocarcinoma ◽  
Pathway Enrichment Analysis ◽  
Metabolome Analysis ◽  
Dismal Prognosis ◽  
Chemotherapeutic Response ◽  
Plasma Metabolome ◽  
Metabolome Profiling

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.

scholarly journals Identification of FEZ2 as a potential oncogene in pancreatic ductal adenocarcinoma

PeerJ ◽  
2022 ◽  
Vol 9 ◽  
pp. e12736
Author(s):  
Chaozhi Yang ◽  
Xuebing Wang ◽  
Chenjie Qiu ◽  
Ziruo Zheng ◽  
Kai Lin ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Malignant Tumors ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Pathway Enrichment Analysis ◽  
Conserved Gene

Pancreatic ductal adenocarcinoma (PDAC) is one of the common malignant tumors with high lethal rate and poor prognosis. Dysregulation of many genes have been reported to be involved in the occurrence and development of PDAC. However, as a highly conserved gene in eukaryotes, the role of Fasciculation and Elongation protein Zeta 2 (FEZ2) in pancreatic cancer progression is not clear. In this study, we identified the oncogenic effect of FEZ2 on PDAC. By mining of The Cancer Genome Atlas (TCGA) database, we found that FEZ2 was upregulated in PDAC tissues and FEZ2 expression was negatively regulated by its methylation. Moreover, high expression and low methylation of FEZ2 correlated with poor prognosis in PDAC patients. Besides, we found that FEZ2 could promote PDAC cells proliferation, migration and 5-FU resistance in vitro. Furthermore, Gene pathway enrichment analysis demonstrated a positive correlation between Wnt signaling activation and FEZ2 expression in PDAC patients. Western blot showed that FEZ2 knockdown significantly suppressed β-catenin expression. Collectively, our finding revealed that FEZ2 functioned as a potential oncogene on PDAC progression and migration, and the expression of FEZ2 had guidance value for the treatment and chemotherapy program of PDAC patients.

scholarly journals Integrated transcriptome meta-analysis of pancreatic ductal adenocarcinoma and matched adjacent pancreatic tissues

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10141
Author(s):  
Sevcan Atay
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Interaction Analysis ◽  
Meta Analysis ◽  
Prognostic Significance ◽  
Enrichment Analysis ◽  
Prognostic Biomarkers ◽  
Ductal Adenocarcinoma ◽  
Receptor Interaction ◽  
Pathway Enrichment Analysis ◽  
Adjacent Tissue

A comprehensive meta-analysis of publicly available gene expression microarray data obtained from human-derived pancreatic ductal adenocarcinoma (PDAC) tissues and their histologically matched adjacent tissue samples was performed to provide diagnostic and prognostic biomarkers, and molecular targets for PDAC. An integrative meta-analysis of four submissions (GSE62452, GSE15471, GSE62165, and GSE56560) containing 105 eligible tumor-adjacent tissue pairs revealed 344 differentially over-expressed and 168 repressed genes in PDAC compared to the adjacent-to-tumor samples. The validation analysis using TCGA combined GTEx data confirmed 98.24% of the identified up-regulated and 73.88% of the down-regulated protein-coding genes in PDAC. Pathway enrichment analysis showed that “ECM-receptor interaction”, “PI3K-Akt signaling pathway”, and “focal adhesion” are the most enriched KEGG pathways in PDAC. Protein-protein interaction analysis identified FN1, TIMP1, and MSLN as the most highly ranked hub genes among the DEGs. Transcription factor enrichment analysis revealed that TCF7, CTNNB1, SMAD3, and JUN are significantly activated in PDAC, while SMAD7 is inhibited. The prognostic significance of the identified and validated differentially expressed genes in PDAC was evaluated via survival analysis of TCGA Pan-Cancer pancreatic ductal adenocarcinoma data. The identified candidate prognostic biomarkers were then validated in four external validation datasets (GSE21501, GSE50827, GSE57495, and GSE71729) to further improve reliability. A total of 28 up-regulated genes were found to be significantly correlated with worse overall survival in patients with PDAC. Twenty-one of the identified prognostic genes (ITGB6, LAMC2, KRT7, SERPINB5, IGF2BP3, IL1RN, MPZL2, SFTA2, MET, LAMA3, ARNTL2, SLC2A1, LAMB3, COL17A1, EPSTI1, IL1RAP, AK4, ANXA2, S100A16, KRT19, and GPRC5A) were also found to be significantly correlated with the pathological stages of the disease. The results of this study provided promising prognostic biomarkers that have the potential to differentiate PDAC from both healthy and adjacent-to-tumor pancreatic tissues. Several novel dysregulated genes merit further study as potentially promising candidates for the development of more effective treatment strategies for PDAC.

scholarly journals New Onset of DiabetEs in aSsociation with pancreatic ductal adenocarcinoma (NODES Trial): protocol of a prospective, multicentre observational trial

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e037267
Author(s):  
Dóra Illés ◽  
Emese Ivány ◽  
Gábor Holzinger ◽  
Klára Kosár ◽  
M Gordian Adam ◽  
...  
Keyword(s):  
High Risk ◽  
Early Detection ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Symptoms ◽  
Risk Group ◽  
High Risk Group ◽  
Ductal Adenocarcinoma ◽  
Onset Diabetes ◽  
Dismal Prognosis ◽  
New Onset

IntroductionPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with an overall 5-year survival of approximately 8%. The success in reducing the mortality rate of PDAC is related to the discovery of new therapeutic agents, and to a significant extent to the development of early detection and prevention programmes. Patients with new-onset diabetes mellitus (DM) represent a high-risk group for PDAC as they have an eightfold higher risk of PDAC than the general population. The proposed screening programme may allow the detection of PDAC in the early, operable stage. Diagnosing more patients in the curable stage might decrease the morbidity and mortality rates of PDAC and additionally reduce the burden of the healthcare.Methods and analysisThis is a prospective, multicentre observational cohort study. Patients ≥60 years old diagnosed with new-onset (≤6 months) diabetes will be included. Exclusion criteria are (1) Continuous alcohol abuse; (2) Chronic pancreatitis; (3) Previous pancreas operation/pancreatectomy; (4) Pregnancy; (5) Present malignant disease and (6) Type 1 DM. Follow-up visits are scheduled every 6 months for up to 36 months. Data collection is based on questionnaires. Clinical symptoms, body weight and fasting blood will be collected at each, carbohydrate antigen 19–9 and blood to biobank at every second visit. The blood samples will be processed to plasma and analysed with mass spectrometry (MS)-based metabolomics. The metabolomic data will be used for biomarker validation for early detection of PDAC in the high-risk group patients with new-onset diabetes. Patients with worrisome features will undergo MRI or endoscopic ultrasound investigation, and surgical referral depending on the radiological findings. One of the secondary end points is the incidence of PDAC in patients with newly diagnosed DM.Ethics and disseminationThe study has been approved by the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (41085-6/2019). We plan to disseminate the results to several members of the healthcare system includining medical doctors, dietitians, nurses, patients and so on. We plan to publish the results in a peer-reviewed high-quality journal for professionals. In addition, we also plan to publish it for lay readers in order to maximalise the dissemination and benefits of this trial.Trial registration numberClinicalTrials.gov NCT04164602

scholarly journals The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment

2020 ◽  
Vol 19 ◽  
pp. 153303382092096
Author(s):  
Hongzhi Sun ◽  
Bo Zhang ◽  
Haijun Li
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stromal Cells ◽  
Genomic Analysis ◽  
Ductal Adenocarcinoma ◽  
Genetic Mutations ◽  
Cellular Processes ◽  
Dismal Prognosis ◽  
Mutant Genes

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

scholarly journals The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3219 ◽  
Author(s):  
Balbina García-Reyes ◽  
Anna-Laura Kretz ◽  
Jan-Philipp Ruff ◽  
Silvia von Karstedt ◽  
Andreas Hillenbrand ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Transcriptional Elongation ◽  
Cyclin Dependent Kinases ◽  
Dismal Prognosis ◽  
The Family ◽  
Cycle Regulation

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.

scholarly journals Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4434
Author(s):  
Siddharth Mehra ◽  
Nilesh Deshpande ◽  
Nagaraj Nagathihalli
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Pi3k Pathway ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Therapeutic Implications ◽  
Downstream Signaling ◽  
Genetic Mouse Model ◽  
Dismal Prognosis ◽  
Effector Pathways

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest solid tumors that remain treatment-refractory and show a dismal prognosis. More than 90% of PDAC tumors harbor mutations in the K-Ras that exert a strong pro-tumorigenic effect by activating several downstream effector pathways, including phosphatidylinositol-3-kinase (PI3K)-Akt. The role of frequently activated PI3K/Akt pathway in promoting PDAC aggressiveness is well established. Therapeutic approaches targeting PI3K and downstream signaling components in different cellular compartments, including tumor, stromal and immune cells, have directly impacted the tumor burden in this cancer type. Our previous work has demonstrated that targeting the PI3K/Akt/mTOR pathway reduced tumor growth and improved survival in the genetic mouse model of PDAC. Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor–stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.

scholarly journals Survival and quality of life following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma

2021 ◽  
Vol 6 (2) ◽  
Keyword(s):  
Quality Of Life ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Short Review ◽  
Mortality Rates ◽  
Ductal Adenocarcinoma ◽  
Term Survival ◽  
Long Term Survival ◽  
Dismal Prognosis

Pancreatic ductal adenocarcinoma (PDAC) most commonly affects the head of the pancreas. This condition has a dismal prognosis. Patients with early disease may be candidates for pancreaticoduodenectomy (PD). This is a high-risk operation which is associated with considerable morbidity. Whilst perioperative mortality rates have fallen in recent times, the risk remains significant and long-term survival is poor, even in those who make an uncomplicated recovery. Furthermore, PD is known to affect quality of life (QoL) negatively. Most studies suggest it takes up to six months before a patient’s QoL returns to baseline. This is a considerable amount of time for a patient who is unlikely to achieve long-term survival. This short review discusses the recent literature surrounding mortality rates, long-term survival and QoL following PD for PDAC. A comprehensive understanding of these topics will allow clinicians and patients to consider the risks and benefits before surgical resection is considered.

Comparison of Pancreatic Ductal Adenocarcinoma Imaging Modalities

2020 ◽  
Vol 6 (4) ◽  
pp. 1-5
Author(s):  
Mohamed Nashnoush
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Sensitivity And Specificity ◽  
Gold Standard ◽  
Epigastric Pain ◽  
Imaging Modality ◽  
Whipple Procedure ◽  
Patient Comfort ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
Highly Sensitive

Pancreatic ductal adenocarcinoma (PDAC) is a fatal type of cancer with an increasing incidence rate in North America. The only curative procedure of this disease is the Whipple procedure, which is restricted only to those that received an early diagnosis. The remainder of the patients are informed of a dismal prognosis and undergo palliative care through systemic chemotherapy. Multiple modalities are involved in the staging and diagnosis of this disease. However, there seems to be a controversy regarding a gold standard or whether a gold standard exists. Additionally, there are various emerging techniques that warrant heightened sensitivity and specificity in their designated modalities. Transabdominal ultrasound that is most commonly used as the first line of imaging for patients with epigastric pain is found to be virtually insensitive to neoplasms that have a size of 2 cm or less, limiting its application. However, sonographers could resort to contrasts and elastography to increase the conspicuity of the neoplasms. Moreover, endoscopic ultrasound has shown to be a promising imaging modality with an unprecedented degree of sensitivity to tumors with a diameter less than 1.5 cm. The sensitivity and specificity values of MDCT, MRI, and PET were found to be comparable. The main conclusions consist of the fact that EUS is a highly sensitive test that should be accompanied by MRI, MDCT, PET, or TUS to increase its specificity. Lastly, empathetic communication is vital not only for patient comfort but also to improve the quality of the imaging assessment.

scholarly journals Pancreatic Ductal Adenocarcinoma (PDAC) Organoids: The Shining Light at the End of the Tunnel for Drug Response Prediction and Personalized Medicine

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2750
Author(s):  
Pierre-Olivier Frappart ◽  
Thomas G. Hofmann
Keyword(s):  
Personalized Medicine ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Drug Response ◽  
Treatment Options ◽  
Response Prediction ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Treatment ◽  
The Past ◽  
Therapeutic Tools ◽  
And Personalized Medicine

Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic malignancies. In contrast to many other tumor entities, the prognosis of PDAC has not significantly improved during the past thirty years. Patients are often diagnosed too late, leading to an overall five-year survival rate below 10%. More dramatically, PDAC cases are on the rise and it is expected to become the second leading cause of death by cancer in western countries by 2030. Currently, the use of gemcitabine/nab-paclitaxel or FOLFIRINOX remains the standard chemotherapy treatment but still with limited efficiency. There is an urgent need for the development of early diagnostic and therapeutic tools. To this point, in the past 5 years, organoid technology has emerged as a revolution in the field of PDAC personalized medicine. Here, we are reviewing and discussing the current technical and scientific knowledge on PDAC organoids, their future perspectives, and how they can represent a game change in the fight against PDAC by improving both diagnosis and treatment options.

scholarly journals The Tumor Microenvironment of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3076
Author(s):  
Eva Karamitopoulou
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Incidence Rates ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
The Future ◽  
Rising Incidence

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis along with rising incidence rates and will be responsible for many cancer deaths in the future [...]

Sign in / Sign up

Export Citation Format

Share Document