scholarly journals Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification

2020 ◽  
Vol 9 (12) ◽  
pp. 4128
Author(s):  
Pilar Espiau-Romera ◽  
Sarah Courtois ◽  
Beatriz Parejo-Alonso ◽  
Patricia Sancho
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Metabolic Profile ◽  
Patient Survival ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Patient Stratification ◽  
Molecular Alterations ◽  
Genomic Signatures ◽  
Amino Acid Consumption ◽  
Acid Consumption

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is an extremely lethal disease due to late diagnosis, aggressiveness and lack of effective therapies. Considering its intrinsic heterogeneity, patient stratification models based on transcriptomic and genomic signatures, with partially overlapping subgroups, have been established. Besides molecular alterations, PDAC tumours show a strong desmoplastic response, resulting in profound metabolic reprogramming involving increased glucose and amino acid consumption, as well as lipid scavenging and biosynthesis. Interestingly, recent works have also revealed the existence of metabolic subtypes with differential prognosis within PDAC, which correlated to defined molecular subclasses in patients: lipogenic subtype correlated with a classical/progenitor signature, while glycolytic tumours associated with the highly aggressive basal/squamous profile. Bioinformatic analyses have demonstrated that the representative genes of each metabolic subtype are up-regulated in PDAC samples and predict patient survival. This suggests a relationship between the genetic signature, metabolic profile, and aggressiveness of the tumour. Considering all this, defining metabolic subtypes represents a clear opportunity for patient stratification considering tumour functional behaviour independently of their mutational background.

scholarly journals Adenosquamous carcinoma of the pancreas harbors KRAS2, DPC4 and TP53 molecular alterations similar to pancreatic ductal adenocarcinoma

2009 ◽  
Vol 22 (5) ◽  
pp. 651-659 ◽  
Author(s):  
Jonathan R Brody ◽  
Christina L Costantino ◽  
Magdalena Potoczek ◽  
Joseph Cozzitorto ◽  
Peter McCue ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Adenosquamous Carcinoma ◽  
Ductal Adenocarcinoma ◽  
Carcinoma Of The Pancreas ◽  
Molecular Alterations

Nuclear UCHL5 Expression Associates with Increased Patient Survival in Pancreatic Ductal Adenocarcinoma

Pancreatology ◽  
2017 ◽  
Vol 17 (3) ◽  
pp. S58-S59
Author(s):  
Kapo Saukkonen ◽  
Leena Arpalahti ◽  
Jaana Hagström ◽  
Harri Mustonen ◽  
Hanna Seppänen ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Survival ◽  
Ductal Adenocarcinoma

Genetic Alterations of K-ras, p53, c-erbB-2, and DPC4 in Pancreatic Ductal Adenocarcinoma and Their Correlation With Patient Survival

Pancreas ◽  
2013 ◽  
Vol 42 (2) ◽  
pp. 216-222 ◽  
Author(s):  
Sang Hyun Shin ◽  
Song Cheol Kim ◽  
Seung-Mo Hong ◽  
Young Hoon Kim ◽  
Ki-Byung Song ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Survival ◽  
Genetic Alterations ◽  
Ductal Adenocarcinoma

scholarly journals KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2429
Author(s):  
Meichen Gu ◽  
Yanli Gao ◽  
Pengyu Chang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Genomic Alteration ◽  
Pancreatic Carcinogenesis ◽  
Novel Method ◽  
Almost All ◽  
Lung Adenocarcinomas

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

scholarly journals The effect of neuroendocrine differentiation on the survival of patients diagnosed with pancreatic ductal adenocarcinoma

2020 ◽  
pp. 38-44
Author(s):  
O. I. Kit ◽  
E. M. Franciyanc ◽  
I. S. Derizhanova ◽  
N. S. Karnaukhov ◽  
M. A. Kuznetsova ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Chromogranin A ◽  
Pancreatic Tumor ◽  
Prognostic Markers ◽  
Patient Survival ◽  
Immunohistochemical Study ◽  
Neuroendocrine Differentiation ◽  
Ductal Adenocarcinoma ◽  
Ki 67 ◽  
Cancer Research Institute

Purpose of the study. Determine the frequency of MiNeN among pancreatic carcinomas and analyze the survival rate of patients depending on the percentage of cells with neuroendocrine differentiation in the tumor.Materials and methods. The current study included 31 patients with a pancreatic tumor who received surgical treatment at the Rostov Cancer Research Institute. An immunohistochemical study was conducted on biomarkers of chromogranin A, synaptophysin, and ki-67 for these patients. Based on the data obtained, 4 groups for neuroendocrine differentiation were identified.Results. The direct effect of neuroendocrine differentiation on the survival of patients with histologically confirmed pancreatic ductal adenocarcinoma has been proven. Among the sample of 31 patients, neuroendocrine differentiation was revealed in 24 cases (77%), of which 3 cases of MiNeN (10.3%) were detected. It is also proven relationship between neuroendocrine and patient survival, where an increase percent of positive cells in tumors (chromogranin A or synaptophysin) means a better prognosis. Chromogranin A is a more significant predictor of survival compared to synaptophysin. The largest difference in survival was between negative expression of chromogranin A and the presence of more than 1% positive cells in the tumor.Conclusion. We supposed that it is necessary to use neuroendocrine markers (chromogranin A and synaptophysin) in the diagnosis of ductal adenocarcinomas, even without histological signs of neuroendocrine differentiation. This will allow for a larger amount of data to determine their significance as prognostic markers.

scholarly journals Identification of the Roles of a Stemness Index Based on mRNA Expression in the Prognosis and Metabolic Reprograming of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Wei Wang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mrna Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Metabolic Pathways ◽  
Gene Set Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Independent Gene ◽  
Gene Modules ◽  
Key Genes

BackgroundCancer stem cells (CSCs) are widely thought to contribute to the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC). CSCs share biological features with adult stem cells, such as longevity, self-renewal capacity, differentiation, drug resistance, and the requirement for a niche; these features play a decisive role in cancer progression. A prominent characteristic of PDAC is metabolic reprogramming, which provides sufficient nutrients to support rapid tumor cell growth. However, whether PDAC stemness is correlated with metabolic reprogramming remains unknown.MethodRNA sequencing data of PDAC, including read counts and fragments per kilobase of transcript per million mapped reads (FPKM), were collected from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD) database. Single-sample gene set enrichment analysis (GSEA) was used to calculate the relative activities of metabolic pathways in each PDAC sample. Quantitative real-time PCR was performed to validate the expression levels of genes of interest.ResultsThe overall survival (OS) of patients with high mRNA expression-based stemness index (mRNAsi) values was significantly worse than that of their counterparts with low mRNAsi values (P = 0.003). This survival disadvantage was independent of baseline clinical characteristics. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and GSEA showed that the differentially expressed genes between patients with high and low mRNAsi values were mainly enriched in oncogenic and metabolic pathways. Weighted gene coexpression network analysis (WGCNA) revealed 8 independent gene modules that were significantly associated with mRNAsi and 12 metabolic pathways. Unsupervised clustering based on the key genes in each module identified two PDAC subgroups characterized by different mRNAsi values and metabolic activities. Univariate Cox regression analysis identified 14 genes beneficial to OS from 95 key genes selected from the eight independent gene modules from WGCNA. Among them, MAGEH1, MAP3K3, and PODN were downregulated in both pancreatic tissues and cell lines.ConclusionThe present study showed that PDAC samples with high mRNAsi values exhibited aberrant activation of multiple metabolic pathways, and the patients from whom these samples were obtained had a poor prognosis. Future studies are expected to investigate the underlying mechanism based on the crosstalk between PDAC stemness and metabolic rewiring.

scholarly journals Serum Metabolomic and Lipoprotein Profiling of Pancreatic Ductal Adenocarcinoma Patients of African Ancestry

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 663
Author(s):  
Nnenna Elebo ◽  
Jones Omoshoro-Jones ◽  
Pascaline N. Fru ◽  
John Devar ◽  
Christiaan De Wet van Zyl ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Survival ◽  
African Ancestry ◽  
Metabolic Phenotype ◽  
Ductal Adenocarcinoma ◽  
Tumour Stage ◽  
Nmr Spectrum ◽  
Spearman’S Correlation ◽  
Patient Survival Time ◽  
Healthy Participants

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses, respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose and lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used to predict patient survival and inform treatment intervention.

Role of the Lymph node ratio in pancreatic ductal adenocarcinoma. Impact on patient stratification and prognosis

2011 ◽  
Vol 104 (6) ◽  
pp. 629-633 ◽  
Author(s):  
Marco La Torre ◽  
Marco Cavallini ◽  
Giovanni Ramacciato ◽  
Giulia Cosenza ◽  
Simone Rossi del Monte ◽  
...  
Keyword(s):  
Lymph Node ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Lymph Node Ratio ◽  
Ductal Adenocarcinoma ◽  
Patient Stratification ◽  
Node Ratio

scholarly journals Snail-Overexpression Induces Epithelial-mesenchymal Transition and Metabolic Reprogramming in Human Pancreatic Ductal Adenocarcinoma and Non-tumorigenic Ductal Cells

2019 ◽  
Vol 8 (6) ◽  
pp. 822 ◽  
Author(s):  
Menghan Liu ◽  
Sarah E. Hancock ◽  
Ghazal Sultani ◽  
Brendan P. Wilkins ◽  
Eileen Ding ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Lactate Production ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cell ◽  
Mesenchymal Transition ◽  
Atp Production ◽  
Ductal Cells

The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic adaptations in different cancers. In the present study, we sought to determine the specific role that Snail has in driving EMT and adaptive metabolic programming in pancreatic ductal adenocarcinoma (PDAC) by overexpressing Snail in a PDAC cell line, Panc1, and in immortalized, non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Snail overexpression was able to induce EMT in both pancreatic cell lines through suppression of epithelial markers and upregulation of mesenchymal markers alongside changes in cell morphology and enhanced migratory capacity. Snail-overexpressed pancreatic cells additionally displayed increased glucose uptake and lactate production with concomitant reduction in oxidative metabolism measurements. Snail overexpression reduced maximal respiration in both Panc1 and HPDE cells, with further reductions seen in ATP production, spare respiratory capacity and non-mitochondrial respiration in Snail overexpressing Panc1 cells. Accordingly, lower expression of mitochondrial electron transport chain proteins was observed with Snail overexpression, particularly within Panc1 cells. Modelling of 13C metabolite flux within both cell lines revealed decreased carbon flux from glucose in the TCA cycle in snai1-overexpressing Panc1 cells only. This work further highlights the role that Snail plays in EMT and demonstrates its specific effects on metabolic reprogramming of glucose metabolism in PDAC.

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