Tissue-resident CXCR4+ macrophage as a poor prognosis signature promotes pancreatic ductal adenocarcinoma progression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE206570 | GEO | 2022/06/24
REPOSITORIES: GEO
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Project description:Tissue-resident CXCR4+ macrophage as a poor prognosis signature promotes pancreatic ductal adenocarcinoma progression
| PRJNA851389 | ENA
Project description:BackgroundEpidermal growth factor receptor (EGFR) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in tumorigenesis and development. However, EGFR expression alone has limited clinical and prognostic significance. Recently, the cross-talk between EGFR and G-protein-coupled chemokine receptor CXCR4 has become increasingly recognized.MethodsIn the present study, immunohistochemical staining of EGFR and CXCR4 was performed on paraffin-embedded specimens from 131 patients with surgically resected PDAC. Subsequently, the associations between EGFR expression, CXCR4 expression, EGFR/CXCR4 coexpression and clinicopathologic factors were assessed, and survival analyses were performed.ResultsIn total, 64 (48.9%) patients expressed EGFR, 68 (51.9%) expressed CXCR4, and 33 (25.2%) coexpressed EGFR and CXCR4. No significant association between EGFR and CXCR4 expression was observed (P = 0.938). EGFR expression significantly correlated with tumor differentiation (P = 0.031), whereas CXCR4 expression significantly correlated with lymph node metastasis (P = 0.001). EGFR/CXCR4 coexpression was significantly associated with lymph node metastasis (P = 0.026), TNM stage (P = 0.048), and poor tumor differentiation (P = 0.004). By univariate survival analysis, both CXCR4 expression and EGFR/CXCR4 coexpression were significant prognostic factors for poor disease-free survival (DFS) and overall survival (OS). Moreover, EGFR/CXCR4 coexpression significantly increased the hazard ratio for both recurrence and death compared with EGFR or CXCR4 protein expression alone. Multivariate survival analysis demonstrated that EGFR/CXCR4 coexpression was an independent prognostic factor for DFS (HR = 2.33, P<0.001) and OS (HR = 2.48, P = 0.001).ConclusionsIn conclusion, our data indicate that although EGFR expression alone has limited clinical and prognostic significance, EGFR/CXCR4 coexpression identified a subset of PDAC patients with more aggressive tumor characteristics and a significantly worse prognosis. Our results suggest a potentially important "cross-talk" between CXCR4 and EGFR intracellular pathways and indicate that the simultaneous inhibition of these pathways might be an attractive therapeutic strategy for PDAC.
| S-EPMC4332630 | biostudies-literature
Project description:Liver kinase B1 (LKB1) has been identified as a critical modulator involved in cell proliferation and polarity. The purpose of the current study was to characterize the expression pattern of LKB1 and assess the clinical significance of LKB1 expression in pancreatic ductal adenocarcinoma (PDAC) patients. LKB1 mRNA expression which was analyzed in 32 PDAC lesions and matched non-tumor tissues, was downregulated in 50% (16/32) of PDAC lesions. Similar results were also obtained by analyzing three independent datasets from Oncomine. Protein expression of LKB1 was significantly reduced in 6 PDAC cell lines and downregulated in 31.3% (10/32) of PDAC lesions compared to matched non-tumorous tissues, as determined by Western blot analysis. Additionally, tissue microarray containing 205 PDAC specimens was evaluated for LKB1 expression by IHC and demonstrated that reduced expression of LKB1 in 17.6% (36/205) of PDAC tissues was significantly correlated with clinical stage, T classification, N classification, liver metastasis and vascular invasion. Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of PDAC and found that LKB1 protein expression was one of the independent prognostic factors for overall survival of PDAC patients.
| S-EPMC4650682 | biostudies-other
Project description:Myeloma Overexpressed (MYEOV) is closely related to cell growth and differentiation in many cancer types. However, the role of this protein-coding gene in pancreatic ductal adenocarcinoma (PDAC) has rarely been investigated. In this study, we demonstrated that MYEOV was higher expressed in tumor tissues compared with adjacent normal pancreas tissues (ANPTs) both in mRNA and protein levels. We also performed bioinformatic analysis and found high MYEOV expression was positively correlated with tumor differentiation (P = 0.004), lymph node metastasis (P = 0.016) and TNM stage (P = 0.001). Moreover, Kaplan-Meier and Cox proportional-hazards analyses indicated that high MYEOV expression was significantly associated with poor survival in patients with PDAC and that MYEOV was an independent prognostic factor for overall survival in patients with PDAC. Geneset Enrichment Analysis (GSEA) result showed that high expression of MYEOV facilitates glycolysis of tumor cells in PDAC and validated in cellular assays. In conclusion, our results suggest that MYEOV acts as an oncogene in PDAC and can therefore serve as a biomarker for the prognosis of patients with PDAC.
| S-EPMC7469688 | biostudies-literature
Project description:Purpose: Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC.Experimental Design: We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production, and growth of PDAC cells in vitro and in vivoResults: p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis.Conclusions: Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing. Clin Cancer Res; 23(7); 1748-59. ©2016 AACR.
| S-EPMC5378683 | biostudies-literature
Project description:During DNA repair, BRCA1 and BRCA2 interact with the tumor suppressor partner and localizer of BRCA2 (PALB2). PALB2 mutations are associated with an increased risk of breast and ovarian carcinoma, and upregulated PALB2 expression is associated with poor clinical outcomes. The present study investigated the role and prognostic value of PALB2 in pancreatic ductal adenocarcinoma (PDAC). PALB2 expression was inhibited using a small interfering RNA in PDAC cell lines, and the subsequent effects on cell proliferation and migration were investigated. Tissue microarrays from 157 patients undergoing a pancreaticoduodenectomy for PDAC were analyzed via immunohistochemistry, and PALB2 expression was compared with patient outcomes using Kaplan-Meier curves and the multivariate Cox regression model. PALB2-knockdown in PDAC cells had little effect on cell proliferation, but significantly decreased cell migration. Relatively high PALB2 expression was observed in PDAC tissues compared with in peritumoral tissues. Overall survival (OS) was negatively associated with PALB2 expression. TNM stage and PALB2 expression were identified as independent prognostic factors associated with OS via multivariate analysis. Overall, the present study demonstrated that PDAC cell migration was dependent on PALB2, which was further supported by the finding that elevated PALB2 expression in PDAC tissues was associated with poor survival in patients with PDAC. Therefore, PALB2 may serve as a novel prognostic marker in PDAC, which may aid with the development of therapeutic strategies for the disease.
| S-EPMC7856690 | biostudies-literature
Project description:BackgroundHIF-1alpha and CAIX proteins are commonly expressed under hypoxic conditions, but other regulatory factors have been described as well. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and strong stromal reaction and has a dismal prognosis with the currently available treatment modalities.MethodsWe investigated the expression and prognostic role of HIF-1alpha and CAIX in PDAC series from Northern Finland (n = 69) using immunohistochemistry.ResultsIn our PDAC cases, 95 and 85% showed HIF-1alpha and CAIX expression, respectively. Low HIF-1alpha expression correlated with poor prognosis, and multivariate analysis identified weak HIF-1alpha intensity as an independent prognostic factor for PDAC-specific deaths (HR 2.176, 95% CI 1.216-3.893; p = 0.009). There was no correlation between HIF-1alpha and CAIX expression levels, and the latter did not relate with survival.ConclusionsOur findings are in contrast with previous research by finding an association between low HIF-1alpha and poor prognosis. The biological mechanisms remain speculative, but such an unexpected relation with prognosis and absence of correlation between HIF-1alpha and CAIX suggests that the prognostic association of HIF-1alpha may not directly be linked with hypoxia. Accordingly, the role of HIF-1alpha might be more complex than previously thought and the use of this marker as a hypoxia-related prognostic factor should be addressed with caution.
| S-EPMC6033289 | biostudies-literature
Project description:Carbohydrate antigen 19-9 (CA19-9) fails to demonstrate the predictive value for early detection pancreatic ductal adenocarcinoma (PDAC). Glypican-1 (GPC1+) exosomes may serve as a noninvasive diagnostic tool to detect early stages of PDAC. Therefore, it is necessary to explore the serum GPC1 levels and determine whether serum GPC1 serves as a novel biomarker for PDAC patients. Blood samples were collected from 156 patients with PDAC, 199 non-cancer controls, and 240 patients with other cancers. Serological levels of GPC1 were examined by enzyme-linked immunosorbent assay (ELISA). Finally, a 5-year follow-up was monitored to evaluate the correlation between serum GPC1 levels and overall survival in 156 patients with PDAC. The results suggested that levels of serum GPC1 and CA19-9 were higher in PDAC patients than that of controls (P < 0.05). Serum GPC1 levels in PDAC were different from those in gallbladder carcinoma (P < 0.001), colorectal carcinoma (P < 0.001), gastric carcinoma (P < 0.001), and prostate cancer (P < 0.001), but not hepatocellular carcinoma (P = 0.395) and cholangiocarcinoma (P = 0.724). Receiver operating characteristic curve (ROC) analysis showed that serum CA19-9 was significantly better than serum GPC1 in distinguishing PDAC patients from the controls (AUC, 95% CI: 0.908, 0.868-0.947 vs 0.795, 0.749-0.841, respectively). The serum GPC1 cannot be used as a serum diagnostic biomarker for PDAC patients. The level of serum GPC1 decreased 2 days after surgery (P = 0.001), which were not different from serum GPC1 levels in healthy control (P = 0.381). The overall survival rate was shorter in patients with high levels of serum GPC1 compared to those with low levels of serum GPC1 (log-rank = 5.16, P = 0.023). Taken together, the results indicate that high levels of serum GPC1 predict poor prognosis in PDAC patients. Serum GPC1 may be a prognosis factor for PDAC patients.
| S-EPMC6246926 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by an important heterogeneity, reflected by different clinical outcomes and chemoresistance. During carcinogenesis, tumor cells display aberrant glycosylated structures, synthetized by deregulated glycosyltransferases, supporting the tumor progression. In this study, we aimed to determine whether PDAC could be stratified through their glycosyltransferase expression profiles better than the current binary classification (basal-like and classical) in order to improve detection of patients with poor prognosis.MethodsBioinformatic analysis of 169 glycosyltransferase RNA sequencing data were performed for 74 patient-derived xenografts (PDX) of resected and unresectable tumors. The Australian cohort of International Cancer Genome Consortium and the microarray dataset from Puleo patient's cohort were used as independent validation datasets.FindingsNew PDAC stratification based on glycosyltransferase expression profile allowed to distinguish different groups of patients with distinct clinical outcome (p-value = 0.007). A combination of 19 glycosyltransferases differentially expressed in PDX defined a glyco-signature, whose prognostic value was validated on datasets including resected whole tumor tissues. The glyco-signature was able to discriminate three clusters of PDAC patients on the validation cohorts, two clusters displaying a short overall survival compared to one cluster having a better prognosis. Both poor prognostic clusters having different glyco-profiles in Puleo patient's cohort were correlated with stroma activated or desmoplastic subtypes corresponding to distinct microenvironment features (p-value < 0.0001). Besides, differential expression and enrichment analyses revealed deregulated functional pathways specific to different clusters.InterpretationThis study identifies a glyco-signature relevant for a prognostic use, potentially applicable to resected and unresectable PDAC. Furthermore, it provides new potential therapeutic targets.FundingThis work was supported by INCa (Grants number 2018-078 and 2018-079), Fondation ARC (Grant number ARCPJA32020070002326), Cancéropôle PACA, DGOS (labelization SIRIC, Grant number 6038), Amidex Foundation and Ligue Nationale Contre le Cancer and by institutional fundings from INSERM and the Aix-Marseille Université.
| S-EPMC8379629 | biostudies-literature
Project description:Controversial data have been reported on the prognostic value of C-X-C motif chemokine receptor 4 (CXCR4) in chronic lymphocytic leukemia (CLL). This prospective, single-center, observational study aimed to evaluate the role of CXCR4 in the pathophysiology of CLL and its prognostic role. A total of 158 patients of CLL were enrolled, and CXCR4 expression on CLL cells was detected by flow cytometry (FCM) at initial diagnosis. The patients were divided into 2 groups according to the CXCR4 mean fluorescence intensity (MFI) median. Also, four patient specimens from the CXCR4low and CXCR4high groups were selected for whole transcriptome sequencing. The progression-free survival (PFS) of CLL patients in the CXCR4high group was significantly shorter than the CXCR4low group, with a median follow-up time of 27 months (log-rank P < 0.001). Moreover, CXCR4 overexpression (MFI > 3376) was an independent marker of poor PFS in CLL patients (P < 0.001). Analysis of whole transcriptome sequencing results revealed that CXCR4 plays an important role in the migration of CLL. Collectively, CXCR4 expression levels on leukemia cells can be detected rapidly by FCM. CXCR4 overexpression was significantly associated with poorer prognosis in CLL patients within a shorter follow-up time.
2024-01-26 | GSE254015 | GEO