scholarly journals Role of N6-methyladenosine Regulated lncRNAs in Prognosis, Tumor Microenvironment and Immune Checkpoints of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Guangzhen Qu ◽  
Dong Wang ◽  
Weiyu Xu ◽  
Wei Guo
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Clustering Algorithm ◽  
Gene Set Enrichment Analysis ◽  
Algorithm Analysis ◽  
Risk Scores ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Term Survival ◽  
Immune Infiltration

Abstract BackgroundThe purpose of this study was to explore the correlation between N6-methyladenosine (m6A)-regulated lncRNAs and tumor prognosis, immune infiltration, immune checkpoints (ICPs) expression in pancreatic ductal adenocarcinoma (PDAC).MethodsWe downloaded the raw RNA-sequence data and clinical data of PDAC from https://xenabrowser.net/ (cohort: TCGA Pancreatic Cancer) and Genotype-Tissue Expression project (GTEx). The m6A-regulated lncRNA was obtained by co-expression analysis. After that, lncRNA profiles and PDAC survival information were merged, and m6A-regulated multi-lncRNA prognostic model was constructed through least absolute shrinkage and selection operator (LASSO) analysis. Through consensus clustering algorithm analysis, PDAC samples were divided into C1 and C2 groups. The downstream pathway signals of the two groups were constructed by Gene set enrichment analysis (GSEA) analysis. Finally, we detect the links between m6A regulated lncRNAs, immune infiltration, immune checkpoint gene expression.ResultsA total of 28 differential expressed m6A-regulated lncRNAs were identified, and based on this, a total of two subtypes of PDAC were obtained. A risk score nomogram consist of 11 m6A-regulated lncRNAs was constructed based on LASSO regression analysis. PDAC patients were divided into low-risk and high-risk groups based on risk scores. In addition to that, we identified IDO1 as a potential novel ICPs in PDAC.ConclusionThis study demonstrates an indispensable role for m6A-regulated lncRNAs in the tumor microenvironment and immune infiltration. We could screen patients suitable for immunotherapy. Long term survival of PDAC patients can be predicted by 11 m6A regulated lncRNAs superiorly. The immune infiltration and ICPs expression were further explored in both groups.

scholarly journals Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Hong Luan ◽  
Chuang Zhang ◽  
Tuo Zhang ◽  
Ye He ◽  
Yanna Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Immune Therapy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Hub Genes ◽  
Immune Infiltration ◽  
The Relationship

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor. The immune profile of PDAC and the immunologic milieu of its tumor microenvironment (TME) are unique; however, the mechanism of how the TME engineers the carcinogenesis of PDAC is not fully understood. This study is aimed at better understanding the relationship between the immune infiltration of the TME and gene expression and identifying potential prognostic and immunotherapeutic biomarkers for PDAC. Analysis of data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases identified differentially expressed genes (DEGs), including 159 upregulated and 53 downregulated genes. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment were performed and showed that the DEGs were mainly enriched for the PI3K-Akt signaling pathway and extracellular matrix organization. We used the cytoHubba plugin of Cytoscape to screen out the most significant ten hub genes by four different models (Degree, MCC, DMNC, and MNC). The expression and clinical relevance of these ten hub genes were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas, respectively. High expression of nine of the hub genes was positively correlated with poor prognosis. Finally, the relationship between these hub genes and tumor immunity was analyzed using the Tumor Immune Estimation Resource. We found that the expression of SPARC, COL6A3, and FBN1 correlated positively with infiltration levels of six immune cells in the tumors. In addition, these three genes had a strong coexpression relationship with the immune checkpoints. In conclusion, our results suggest that nine upregulated biomarkers are related to poor prognosis in PDAC and may serve as potential prognostic biomarkers for PDAC therapy. Furthermore, SPARC, COL6A3, and FBN1 play an important role in tumor-related immune infiltration and may be ideal targets for immune therapy against PDAC.

scholarly journals Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hong-Bo Li ◽  
Zi-Han Yang ◽  
Qing-Qu Guo
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Immune Effector ◽  
Effector Cells ◽  
Pathological Subtype

AbstractPancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting.

scholarly journals Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

2021 ◽  
Vol 22 (24) ◽  
pp. 13408
Author(s):  
Utpreksha Vaish ◽  
Tejeshwar Jain ◽  
Abhi C. Are ◽  
Vikas Dudeja
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tumor ◽  
Therapeutic Strategies ◽  
Ductal Adenocarcinoma ◽  
Western World ◽  
Significant Heterogeneity ◽  
Cancer Associated Fibroblasts ◽  
Term Survival

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

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 Mast Cells in Tumor Microenvironment Promotes the In Vivo Growth of Pancreatic Ductal Adenocarcinoma

2011 ◽  
Vol 17 (22) ◽  
pp. 7015-7023 ◽  
Author(s):  
David Z. Chang ◽  
Ying Ma ◽  
Baoan Ji ◽  
Huamin Wang ◽  
Defeng Deng ◽  
...  
Keyword(s):  
Mast Cells ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
In Vivo Growth

scholarly journals Vascular resection for locally advanced pancreatic ductal adenocarcinoma: analysis of long-term outcomes from a single-centre series

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Claudio F. Feo ◽  
Giulia Deiana ◽  
Chiara Ninniri ◽  
Giuseppe Cherchi ◽  
Paola Crivelli ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Locally Advanced ◽  
Operating Time ◽  
Vascular Resection ◽  
Ductal Adenocarcinoma ◽  
Term Survival ◽  
Aggressive Approach ◽  
Long Term Survival ◽  
Cox Regression Analysis

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis. Radical surgery is the best option for cure and, nowadays, it is performed by many surgeons also in cases of vascular infiltration. Whether this aggressive approach to a locally advanced PDAC produces a survival benefit is under debate. Most data in the literature come from retrospective comparative studies; therefore, it is still unclear if such an extensive surgery for an advanced cancer is justified. Methods A retrospective review of patients with PDAC treated at our institution over a 12-year period was performed. Data concerning patients’ characteristics, operative details, postoperative course, and long-term survival were retrieved from prospective databases and analysed. Factors associated with poor survival were assessed via Cox regression analysis. Results A total of 173 patients with PDAC were included in the analysis, 41 subjects underwent pancreatectomy with vascular resection for locally advanced disease, and in 132 patients, only a pancreatic resection was undertaken. Demographics, major comorbidities, and tumour characteristics were similar between the two groups. Length of surgery (P=0.0006), intraoperative blood transfusions (P<0.0001), and overall complications (P<0.0001) were significantly higher in the vascular resection group. Length of hospital stay (P=0.684) and 90-day mortality (P=0.575) were comparable between groups. Overall median survival (P= 0.717) and survival rates at 1, 3, and 5 years (P=0.964, P=0.500, and P=0.445, respectively) did not differ significantly between groups. Age ≥70 years and postoperative complications were independent predictors of lower survival. Conclusions Our study confirms that pancreatectomy with vascular resection for a locally advanced PDAC is a complex operation associated with a significant longer operating time that may increase morbidity; however, in selected patients, R0 margins can be obtained with an acceptable long-term survival rate. Older patients are less likely to benefit from surgery.

scholarly journals Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

2020 ◽  
Author(s):  
S. Mahnaz ◽  
L. Das Roy ◽  
M. Bose ◽  
C. De ◽  
S. Nath ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Transmembrane Glycoprotein ◽  
The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

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.

Abstract PO-115: Effects of mesothelin exert on tumor microenvironment in pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Dongliang Liu ◽  
Ethan Poteet ◽  
Zhengdong Liang ◽  
Emily Laplante ◽  
Lisa Brubaker ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma
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