Expression data from advanced stage of murine pancreatic ductal adenocarcinoma (PDAC) and control pancreas
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Sophie Vasseur
PROVIDER: E-GEOD-61412 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:A major impediment to the effective treatment of patients with PDAC (Pancreatic Ductal Adenocarcinoma) is the molecular heterogeneity of the disease, which is reflected in an equally diverse pattern of clinical responses to therapy. We developed an efficient strategy in which PDAC samples from 17 consecutively patients were obtained by EUS-FNA or surgery, their cells maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. For these patients a clinical follow up was obtained. On the breathing tumors we studied the RNA expression profile by an Affymetrix approach. We observed a significant heterogeneity in their RNA expression profile, however, the transcriptome was able to discriminate patients with long- or short-time survival which correspond to moderately- or poorly-differentiated PDAC tumors respectively. Cells allowed us the possibility to analyze their relative sensitivity to several anticancer drugs in vitro by developing a chimiogram, like an antibiogram for microorganisms, with several anticancer drugs for obtaining an individual profile of drug sensitivity and as expected, the response was patient-dependent. Interestingly, using this approach, we also found that the transcriptome analysis could predict the sensitivity to some anticancer drugs of patients with a PDAC. In conclusion, using this approach, we found that the transcriptome analysis could predict the sensitivity to some anticancer drugs and the clinical outcome of patients with a PDAC. PDAC samples from 17 consecutively patients were obtained by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery. Consents of informed patients were collected, and the ethics review board of the three centers approved the study. All samples were anonymized and obtained in accordance with institutional review boards. EUS-FNA cells were maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. We characterized 17 PDAC-derived xenografts by duplicate. Total RNA was extracted and hybridized on Human Gene 2.0 (Genechip, Affymetrix) as described previously (Hamidi et al. JCI 122: 2092-2103, 2012).
2015-04-09 | E-GEOD-55513 | biostudies-arrayexpress
Project description:Pancreatic adenocarcinoma (PDAC) is an extremely deadly disease for which all treatments available have failed to improve life expectancy significantly. This may be explained by the high metastatic potential of PDAC cells, which results from their physiological dedifferentiation towards a mesenchymal phenotype. Some PDAC present cell-in-cell structures but their origin and significance is currently unknown. We show here that cell-incells form after cell cannibalism. We found PDAC patients whose tumors display cell cannibalism develop less metastasis than those without. In vitro, cell cannibalism was enhanced by the TGFM-NM-2 and repressed by the Nuclear protein (Nupr)1, and was coupled to a defective epithelial-to-mesenchymal transition of PDAC cells. Cannibalism ends with death of PDAC cells, consistent with a metastasis suppressor role for this phenomenon. Hence, our data indicates a protective role for cell cannibalism in PDAC and identifies Nupr1 and TGFM-NM-2 as molecular regulators of this process. Cell culture and culture reagents. Panc-1 cells were cultured in Glutamax-containing DMEM(Invitrogen) and BxPC3 in RPMI (Invitrogen), both supplemented with 10% FBS (PAA Laboratories). All cells were maintained at 37M-BM-0C, 5% CO2, H2O saturated. TGFM-NM-21 (Peprotech) was used at 10 ng/ml .siRNA-mediated gene silencing. Panc-1 cells were seeded in 6-wells plates to reach 30% to 50% confluence. Twenty-four hours later, a mix containing 2.2 pmoles of siRNA and 8 M-NM-<l of the transfection reagent INTERFERIN (Polyplus Transfection) was added to the culture medium according to manufacturerM-bM-^@M-^Ys instructions. Panc-1 Nupr1-depleted cells (sip8), and controls cells (siCtrl) were further incubated for 7 or 24 hrs before TGFM-NM-21 treatment without change of medium.
2012-06-17 | E-GEOD-38772 | biostudies-arrayexpress
Project description:Pancreatic Ductal Adenocarcinoma (PDA) is a critical health issue in cancer field with little new therapeutic options. Several evidences support an implication of intra-tumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within pathophysiology and clinical course of PDA, mainly through tumor recurrence and neuropathic pain, remains unknown neglecting a putative therapeutic window. Here, we report that intra-tumoral microenvironment is a mediator of PDA Associated Neural Remodeling (PANR). With laser capture microdissection of stromal/tumoral compartment from human PDA followed by cDNA based microarray analyses we highlighted numerous factors expressed by stromal compartment that could impact on neuroplastic changes; among them, the Slit2/Robo axon guidance pathway. Using co-culture in vitro, we showed that stromal secreted Slit2 increases DRG neurite outgrowth and Schwann cells migration/proliferation by modulating N-Cadherin/β-Catenin signaling. Importantly, Slit2/Robo signaling inhibition disrupts this stromal/neural connection. Finally, we revealed in vivo that Slit2 expression is correlated with neural remodeling within Human and mouse PDA. These results demonstrate the implication of microenvironment, through secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of stromal/neural compartment dialogue by using Slit2/Robo pathway inhibitors for treatment of pancreatic cancer recurrence and associated pain. Freshly frozen tissue samples of PDACs were obtained from patients who underwent surgery. Patients underwent hemipancreaticoduodenectomy or distal pancreatectomy. No distant metastases were revealed at initial diagnosis. Histological examination confirmed diagnosis of PDAC in all cases. Prior to surgery all patients had signed an informed consent form that had been approved by the local ethics committee. Frozen sections were obtained from tissue samples of three tumors. After a brief staining sections were dehydrated and epithelial and stromal compartment has been microdissected using the PALM system. The microdissected material was immediately dissolute in a buffer containing β-mercaptoethanol and RNA carrier, and frozen before RNA extraction. Fifteen ug of total RNA was converted to biotinylated cRNA and hybridised to a human oligonucleotide array U133 Plus 2.0 (Genechip, Affymetrix, Santa Clara, CA).
2015-07-01 | E-GEOD-50570 | biostudies-arrayexpress
Project description:We used microarrays to detail the global gene expression signature of PDAC and to identify distinct up- and down-regulated transcripts in these tumors compared to control pancreas. We also established from this dataset the metabolic signature of PDAC in order to define new metabolic therapeutic target for pancreatic cancer.
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Project description:We used microarrays to detail the global gene expression signature of PDAC and to identify distinct up- and down-regulated transcripts in these tumors compared to control pancreas. We also established from this dataset the metabolic signature of PDAC in order to define new metabolic therapeutic target for pancreatic cancer.
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Project description:Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure and increased susceptibility to cancer. Of the fifteen FA proteins, Fanconi anemia group C (FANCC) is one of eight FA core complex components of the FA pathway. Unlike other FA core complex proteins, FANCC is mainly localized in the cytoplasm, where it is thought to function in apoptosis, redox regulation, cytokine signaling and other processes. Previously, we showed that regulation of FANCC involved proteolytic processing during apoptosis. To elucidate the biological significance of this proteolytic modification, we searched for molecular interacting partners of proteolytic FANCC fragments. Among the candidates obtained, the transcriptional corepressor protein C-terminal binding protein-1 (CtBP1) interacted directly with FANCC and other FA core complex proteins. Although not required for stability of the FA core complex or ubiquitin ligase activity, CtBP1 is essential for proliferation, cell survival and maintenance of chromosomal integrity. Expression profiling of CtBP1-depleted and FA-depleted cells revealed that several genes were commonly up- and down-regulated, including the Wnt antagonist Dickkopf-1 (DKK1). These findings suggest that FA and Wnt signaling via CtBP1 could share common effectors. HeLa cell line was grown in DMEM media supplemented with 10% FBS and were incubated in 5% CO2 at 37°C. A four-plasmid (pRSV-Rev, pMDLg/pRRE, pMD2.G and pLKO.1) expression system was used for lentiviral production. Different pLKO.1 plasmids carrying shRNAs targeting FANCA, FANCD2, CtBP1 or CtBP2 or a lentiviral control vector pLKO.1-scrambled were used. Lentiviral particles were produced via calcium phosphate-mediated transient transfection of the four plasmids into HEK293T cells. Cells were exposed to appropriate lentiviral particles. In each experiment, HeLa cells were transduced for 6 hours with filtered supernatant containing recombinant lentiviral particles. After transduction, the cells were cultured for 72 hours. Total RNA extracts from 3 different samples of each scrambled, CtBPs and FANCD2 shRNA treated HeLa cells were subjected to gene expression profiling via microarray analysis. Gene expression profiles were determined with Affymetrix GeneChip® Human Gene 1.0.
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