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Expression analysis of a preinvasive pancreatic cancer mouse model with and without p120 catenin

ABSTRACT: Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia.

ORGANISM(S): Mus musculus

PROVIDER: GSE68090 | GEO | 2016/07/25

SECONDARY ACCESSION(S): PRJNA281710

REPOSITORIES: GEO

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Expression analysis of a preinvasive pancreatic cancer mouse model with and without p120 catenin

Project description:Pancreatic cancer is one of the most deadly cancers with a 5 year survival rate of about 5%. Therapeutic options are limited, especially for patients that present with late state disease and metastasis. Although the metastatic burden of pancreatic cancer is usually high, little is known about the mechanisms that regulate delamination and dissemination of epithelial cells from preinvasive and malignant pancreatic lesions. Here, we used a preinvasive mouse model of pancreatic cancer to conditionally knockout p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1P2 signaling. Our results establish p120 catenin and S1P/S1P2 signaling as novel regulators of non-EMT mediated epithelial cell invasion in pancreatic neoplasia. Transcriptomes of KCiMist1G; p120wt/wt and KCiMist1G; p120f/f pancreases were compared, with three replicates each, using microarray.

2016-07-25 | E-GEOD-68090 | biostudies-arrayexpress

Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia

Project description:Many human cancers are dramatically accelerated in the setting of chronic inflammation. However the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN cells, and stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by chronic pancreatitis, resulting in functional in vivo changes in gene expression among PanIN epithelial cells. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.

2016-02-03 | GSE54753 | GEO

Mus musculus

Project description:Expression analysis of a preinvasive pancreatic cancer mouse model with and without p120 catenin

| PRJNA281710 | ENA

Induced Pluripotent Stem Cells From Pancreatic Ductal Adenocarcinoma Can Recapitulate Early Developmental Stages of Cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of any human malignancy and there are few human cellular models of disease progression. When human PDAC cells are injected into immunodeficient animals, they create tumors of the late stage from which they were derived. We hypothesized that if human pancreatic cancer cells were converted to pluripotency and then allowed to differentiate back into pancreas, the developmental progression would recapitulate early stages of the cancer. To that end, we have generated isogenic matched sets of induced pluripotent stem (iPS) cell-like lines from epithelial cells of human pancreatic tumors and from histologically normal epithelial cells at the resected pancreatic margins. Notably, when injected into immunodeficient mice, at low or high passages, a human pancreatic cancer iPS-like line, but not the corresponding margin iPS-like line, slowly generates intra-epithelial neoplasia (PanIN) ductal structures that typically reflect the early stages of human pancreatic cancer. The PanIN-like ducts can be isolated and cultured. They secrete protein products reflective of PanINs and provide new insights into underlying regulatory networks. An additional iPS-like line from histologically normal cells at a pancreatic resection margin, but containing a mutation that predisposes to PDAC, does not generate PanIN ductal structures. These studies demonstrate that iPS technology can be exploited to recapitulate early progression events of a human epithelial cancer. Study includes a single experiment (#10): a tumor-adjacent pancreatic tissue control (10N); tumor tissue (10C); IPS-transformed tissue control (10N12); and IPS-transformed tumor tissue (10C22).

2013-06-20 | E-GEOD-47985 | biostudies-arrayexpress

Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues

Project description:The aim of this experiment is to unravel PDAC biology and phospho-print based on aberrant kinase activities and proteome alterations. For this we will perform pTYyrIP, Bravo_IMAC, and protein expression data of n=56 tissues encompassing 47 pancreatic ductal adenocarcinoma (PDAC), 5 cholangiocarcinoma, 1 Intraductal Papillary Mucinous Neoplasm (IPMN), 1 pancreatitis and 1 pancreatitis-Pancreatic Intraepithelial Neoplasia (PanIN) tissue. Pancreatitis, PanIN, and IPMN are seen as early events predecessing PDAC. An equiproportional pool of 5 PDAC cell lines (PANC1, SUIT-2, CFPAC-1, HPAC, MIAPACA2) is also taken along.

2024-04-23 | PXD043111 | Pride

Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells

Project description:Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. After pancreatic transplantation, mutant clones form lesions histologically similar to native PanINs, including prominent stromal responses. Gene expression profiling reveals molecular similarities of mutant clones with native PanINs, and identifies potential PanIN biomarker candidates including Neuromedin U, a circulating peptide hormone. Prospective reconstitution of human PanIN development from primary cells provides experimental opportunities to investigate pancreas cancer development, progression and early-stage detection.

2017-03-14 | GSE88997 | GEO

Induced Pluripotent Stem Cells From Pancreatic Ductal Adenocarcinoma Can Recapitulate Early Developmental Stages of Cancer

2013-06-20 | GSE47985 | GEO

p120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals

Project description:The Adherens Junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120-catenin regulates the intrinsic migratory properties or primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA-GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell motility via increase of actin stress fibers, reduction in integrin turnover, and an increase in focal adhesions robustness. The other is coupled to the secretion of inflammatory cytokines including Interleukin-24, which causally enhances randomized cell movements. Taken together, our results indicate that p120-RhoA-GTPase-mediated signaling can differentially regulate the migratory behavior of epidermal cells, which has potential implications for chronic wound responses and cancer.

2016-12-31 | GSE55019 | GEO

Identification of transcriptional signatures overlapping in pancreatic ductal development, acute pancreatitis and KrasG12D-driven carcinogenesis

Project description:To determine the molecular basis of gene regulation in pancreatic ductal epithelial cells, we developed methods for the isolation of this cell population during mouse development and normal adult homeostasis, as well as in conditions with ductal features (acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC)). Our technique utilizes the specificity of Dolichos biflorus Agglutinin (DBA) lectin marking the entire normal ductal tree, including terminal intercalated ducts (putative sites of stem or progenitor cells) and ductal structures in ADM and PanIN. We used ferromagnetic-labeled DBA lectin to isolate ductal structures. Ductal cells were isolated under the following conditions: (1) Embryonic Development in wild type mice: E14.5, E15.5, E16.5, and postnatal day 1 (P1); (2) Injury and regeneration (pancreatitis) 0, 1, 3, 5 days following cerulein-induced acute pancreatitis. Cerulein is a cholecystokinin analog which produces a self-limited pancreatitis with injury and subsequent regeneration and repair, completed five days after insult; and (3) Pdx1-Cre;LSL-KrasG12D/+ mice aged 10 and 20 weeks that harbor PanIN lesions and a subset develop PDAC. Ductal/PanIN cells were isolated from these mice and appropriate control mice (Pdx1-Cre;Kras+/+).

2015-09-30 | GSE40895 | GEO

Investigate the role of Wnt/beta-catenin signaling in development of the exocrine pancreas

Project description:beta-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of beta-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that beta-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of beta-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of beta-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of beta-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed beta-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis. Keywords: Time course

2007-04-04 | GSE7430 | GEO

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