Proteomic Landscape of Pancreatic Cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Janne Lehtiö
PROVIDER: PXD025120 | JPOST Repository | Fri May 20 00:00:00 BST 2022
REPOSITORIES: jPOST
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Project description:Purpose: To study the expression and function of a novel cell cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer (PC) pathogenesis. Experimental Design: Immunohistochemical expression profiling of Ecd was done in non-neoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in PC progression, Ecd was stably knocked down in PC cell line followed by in vitro and in vivo functional assays. Results: Normal pancreatic ducts show very weak to no Ecd expression compared to significant positive expression in PC tissues (mean±SE composite score: 0.3±0.2 and 3.8±0.2 respectively, p<0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1 to PanIN-3). Analysis of matched primary tumors and metastases from PC patients revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Further, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of PC cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in PC cells and was subsequently shown to modulate glucose uptake, lactate production and ATP generation by PC cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells. Conclusion: Ecd is a novel tumor promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells. Two-condition experiment, Ecd knockdown vs Scrambled cells. Biological replicates: 3 Ecd knockdownl, 3 Scrambled, independently grown and harvested. One replicate per array
2012-08-09 | E-GEOD-39988 | biostudies-arrayexpress
Project description:Purpose: To study the expression and function of a novel cell cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer (PC) pathogenesis. Experimental Design: Immunohistochemical expression profiling of Ecd was done in non-neoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in PC progression, Ecd was stably knocked down in PC cell line followed by in vitro and in vivo functional assays. Results: Normal pancreatic ducts show very weak to no Ecd expression compared to significant positive expression in PC tissues (mean±SE composite score: 0.3±0.2 and 3.8±0.2 respectively, p<0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1 to PanIN-3). Analysis of matched primary tumors and metastases from PC patients revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Further, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of PC cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in PC cells and was subsequently shown to modulate glucose uptake, lactate production and ATP generation by PC cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells. Conclusion: Ecd is a novel tumor promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells.
2012-08-10 | GSE39988 | GEO
Project description:Pancreatic cancer (PC) is the third deadliest malignancy with a dismal five-year survival rate. The KrasG12D initiator mutation, present in 95% of the PC patients, leads to the development of pancreatic intraepithelial neoplasia (PanIN). The PanIN lesions, the most common precursor lesion of PC, exhibit de novo expression of mucins, which significantly contributes to PC pathobiology. The poor clinical outcome of PC warrants the identification of molecular player(s) that facilitate the progression of Kras-driven precursor lesions to invasive ductal carcinoma. Gel-forming mucin 5AC (MUC5AC) is one of the top differentially expressed genes in PC as compared to the normal pancreas. The expression of MUC5AC appears de-novo at PanIN-1A stage and elevates in tumor tissues, while remaining absent in the normal pancreas. To delineate the mechanistic contribution of Muc5ac in PC pathology, we genetically depleted Muc5ac in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of PC. The onset of neoplastic growth and the progression of low-grade to high-grade PanIN lesions were significantly delayed in Muc5ac knockout (KrasG12D; Muc5ac-/-; Pdx-1cre, KCM) animals. We utilized high-throughput RNA seq. analysis to investigate the downstream molecular targets of Muc5ac-associated PC progression. Our study demonstrated that knockout of Muc5ac led to a significant decline in the genes associated with cancer stem cell (CSC) maintenance and epithelial-to-mesenchymal transition (EMT). The contribution of MUC5AC in CSC maintenance was validated via in vitro experiments, and tumor formation frequency using limiting dilution assay upon subcutaneous administration.
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Project description:Age-standardized incidence rates for pancreatic cancer (PC) in men have increased by 25% from 1957 to 2011 in Finland. The average age of diagnosis for PC is 69 years in Nordic males, whereas the average age of diagnosis of chronic pancreatitis (CP) is 40-50 years, but the cases overlap in age. By radiology the evaluation of a pancreatic mass, i.e. the differential diagnosis between CP and PC is often difficult. Preoperative needle biopsies are difficult to obtain and are demanding to interpret. New blood based biomarkers are needed. The accuracy of the only established biomarker for PC, CA 19-9 is rather poor in differentiating between benign and malignant mass of the pancreas. In this study, we have performed mass spectrometry HDMSE analysis of serum samples from patients with chronic pancreatitis and pancreatic cancer. We have quantified 652 proteins and performed detailed statistical analysis such as principal component analysis, orthogonal partial least square discriminant analysis and receiver operating curve analysis.
2017-06-09 | PXD005144 | Pride
Project description:The goal of the experiment was to explore the differences in the proteomic landscape of pancreatic cancer tissues collected by the Rapid Autopsy Program at UNMC. We hypothesized the proteomic profile can reflect some of the clinical features observed in the patient, and such information can be used for the diagnosis of the disease, or assisting in the selection of treatment options in a clinical setting. The liver metastases tissue collected from 59 pancreatic cancer patients were used to explore the proteomic landscape. 56 of these patients were diagnosed with pancreatic ductal adenocarcinoma (PDAC) and 3 of them had pancreatic neuroendocrine tumors (PanNET). The additional 9 primary tumor samples analyzed are included in this project.
2019-11-18 | PXD015492 | Pride
Project description:Genome-wide DNA methylation profiling of normal and tumor tissue samples of 7 pancreatic ductal adenocarcinoma patients.
2022-11-09 | GSE181740 | GEO
Project description:While of growing interest in pancreatic cancer (PC) field, the stromal-tumor cells crosstalk lags behind in terms of biomarkers and therapeutic options improving the clinical armamentarium. Knowledge on cellular communications was drastically enhanced following the discovery of extracellular vesicles (EVs), a powerful process of intercellular exchanges. We previously described a new stromal-tumor cell crosstalk mediated by Cancer-Associated Fibroblasts (CAFs)-derived ANXA6+-EVs, supporting pancreatic cancer cell aggressiveness in hostile areas of PC. In this study, using mass spectrometry analyses to investigate CAFs-derived EVs' cargo, we report that CD9 is a key member of the ANXA6/LRP1/TSP1 complex present in PC-associated CAFs-derived ANXA6+-EVs. We determined that CD9 is expressed by PC-associated CAFs in vivo as well as in vitro following physiopathologic culture conditions. Targeting CD9 impaired CAFs-derived ANXA6+-EVs uptake by pancreatic cancer cells, which consequently decreases their migratory abilities. Signaling pathway arrays highlighted p38/MAPK as activated in pancreatic cancer cells following CAFs-derived ANXA6+/CD9+-EVs uptake. The use of CD9 blocking antibody, p38 siRNA or chemical inhibitors impaired pancreatic cancer cells abilities following incubation with CAFs-derived ANXA6+/CD9+-EVs. Finally, we revealed CD9 expression as an independent poor-prognosis marker in human PC samples. Collectively our data highlight the key role of CD9 in CAFs-derived ANXA6+-EVs internalization by pancreatic cancer cells and the consequent, and mandatory, activation of p38/MAPK pathway to foster their migratory abilities. Measuring the oncogenic CAFs-derived ANXA6+/CD9+-EVs then limiting their action on pancreatic cancer cells abilities might be a promising option for PC stratification and treatment.
2022-08-21 | PXD023165 | Pride
Project description:In this study, we used RNA-seq to investigate the transcriptomic (mRNA and miRNA) profiles of pancreatic cancer in 10 paired tumor and normal pancreatic samples from patients
2018-09-12 | GSE119794 | GEO
Project description:Pancreatic Cancer (PC) remains highly lethal due to limited therapeutic options. Here we utilize a genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting. ISOX emerged as a top potential drug from the CMAP pipeline across human PC tissues, cell lines, tumoroids, and patient-derived xenografts datasets. Here, we use PC cells, human and mouse tumoroids, and in vivo mouse models to test the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Transcriptomic and pathway analysis of the ISOX-LINCS signature identified the various pathways as targets for ISOX, suggesting a multiple-target action. Specifically, we discovered that genetic and pharmacological targeting of HDAC6 affected non-histone protein cMYC acetylation leading to cMYC instability, thereby disrupting PC stem cells. Finally, KrasG12D harboring organoids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a novel drug to treat advanced PC patients without toxicity to normal cells
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Project description:Expression profiling of 8 normal pancreatic and 14 PDAC tissues. Data was generated from Affymetrix arrays. Results provide a global profile of over 50,000 genes in normal and tumorous tissues, and comparison of the differentially expressed genes between the normal and tumor groups. Gene expression was profiled and compared between normal pancreatic and PDAC RNA samples globally, using Affymetrix GeneChip® Human Genome U133 Plus 2.0array.
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