Longitudinal analysis of pancreatic adenocarcinoma development reveals transient gene expression signatures (I. 10-22 cell RNA-Seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE173489 | GEO | 2022/04/01
REPOSITORIES: GEO
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Project description:We performed a transcriptome time-course analysis of genetically tagged human PDAC cells reprogrammed into a pluripotent stem cell-like line (10-22 cells) through the progression from PanINs to PDAC in mice. The results were validated using the Cancer Genome Atlas (TCGA) PDAC dataset, human clinical PanIN/PDAC tissues, and well-established murine PDAC model. Human normal pancreatic ductal epithelial cell line (H6C7) and PDAC cell lines (Miapaca2, Aspc1) are used for functional validation of HBP1. Pathways for extracellular vesicle transport pathways and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. Analysis of transcription factor (TF) motifs at dynamically expressed genes revealed roles for HBP1 and BACH during PDAC progression and their inverse correlations with PDAC patients' prognosis. Notably, we detected gene activity changes that were transient during PDAC progression. Our longitudinal analysis provides insights into networks underlying PDAC progression and pathogenesis.
2022-04-01 | GSE173286 | GEO
Project description:Background: With less than a 5% survival rate pancreatic adenocarcinoma (PDAC) is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical. Methods and Findings: We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses. Conclusions: Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic pancreatic adenocarcinoma. Gene expression of 13 PanIN samples was compared to profiling data of whole biopsies from normal donor pancreas (N1 to 4, two replicated samples) and sporadic PDAC (PDAC1 to 6).Ttwo PDAC samples (PDAC 3 and 4) and a replicate of one normal specimen (N4) were removed during the hybridisation quality assessment.
2013-03-27 | E-GEOD-43288 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is believed to arise from the accumulation of a series of somatic mutations and is also frequently associated with pancreatic intraepithelial neoplasia (PanIN) lesions. However, there is still debate as to whether the cell-type-of-origin of PanINs and PDACs is acinar or ductal. As cell type identity is maintained epigenetically, DNA methylation changes during pancreatic neoplasia can provide a compelling perspective to examine this question, but DNA methylation sequencing has not yet been performed genome-wide on purified exocrine and neoplastic cell types in the pancreas. Thus, we performed genome-wide DNA methylation sequencing on acini, non-neoplastic ducts, PanIN lesions, and PDAC lesions. We found that: 1) both global methylation profiles and block DMRs clearly implicate an acinar origin for PanINs; 2) at the gene level, PanIN lesions exhibit an intermediate acinar-ductal phenotype resembling acinar-to-ductal metaplasia (ADM); and 3) PanINs are epigenetically primed to progress to PDAC. Thus, epigenomic analysis complements histopathology to define molecular progression toward PDAC.
2023-05-08 | GSE222147 | GEO
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
Project description:Background: With less than a 5% survival rate pancreatic adenocarcinoma (PDAC) is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical. Methods and Findings: We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses. Conclusions: Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic pancreatic adenocarcinoma.
2013-03-27 | GSE43288 | GEO
Project description:The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant – p5353,54 – which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. We find that p5353,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC.
2023-02-12 | GSE224744 | GEO
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.
2013-06-20 | GSE47985 | GEO
Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here we determine the contribution of epigenetically silenced genes to the development of PDAC. METHODS: We investigated methylated DNAs from PDACs, chronic pancreatitis and normal pancreatic tissues using Methyl-CpG immunoprecipitation followed by microarray hybridization. Promoter methylation of selected genes was confirmed with the Epityper assay. Expression levels were evaluated by quantitative RT-PCR. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanINs), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. RESULTS: A total of 3.8% of 27.800 interrogated CpG islands were hypermethylated in PDAC versus normal and chronic pancreatitis tissues. Hypermethylation was confirmed in 12 out of 13 selected islands and was associated with gene silencing in 4 of them. The most prominently hypermethylated gene, WNK2, was further investigated. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in pancreatic tumor cells than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expression were lower in PDAC and chronic pancreatitis compared to normal tissues both in patients and mouse models. Overexpression of WNK2 led to a reduced cell growth and WNK2 expression in tissues correlated negatively with the expression of pERK1/2, a downstream target of WNK2 responsible for cell proliferation. CONCLUSIONS: WNK2 is downregulated by promoter hypermethylation early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. 3 types of pancreatic tissue samples: 5 normals, 2 chronic pancreatitis, 7 tumors (PDAC)
2012-11-01 | E-GEOD-37480 | biostudies-arrayexpress
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
Project description:Nuclear Protein 1 (Nupr1) is a major actor of the cell stress response required for KrasG12D-driven formation of pancreatic intraepithelial neoplastic (PanINs) lesions in mice. We investigated the impact of Nupr1-depletion on the development and biology of murin pancreatic adenocarcinomas (PDAC) in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mice. We found that only one half of Nupr1-deficient mice developed PDAC. This is related to increased caspase 3 activity and low IER3 expression in Nupr1-deficient;KIC in the pancreas. Moreover, when Nupr1-deficient;KIC mice do develop PDAC, tumors present with impaired epithelial-to-mesenchymal transition (EMT). Transcriptoma analysis revealed that Nupr1-deficient and Nupr1wt;KIC PDACs presented enrichment of gene signatures of the human classical- and quasi-mesenchymal (QM)-PDAC respectively. Moreover, Nupr1-deficient;KIC PDACs shared with human classical-PDACs overexpression of Kras-activation genes. In addition, cells derived from Nupr1-deficient;KIC PDACs formed fewer microspheres in vitro compared to Nupr1wt;KIC cells, indicative of stemness impairment in the absence of Nupr1. Finally, we found that Nupr1-deficient;KIC cells were more sensitive to some anticancer drugs than their Nupr1wt counterpart. Hence, this study establishes the pivotal role of Nupr1 in PDAC progression after PanIN and in PDAC EMT in vivo, with an impact in PDAC cell stemness. As a consequence, according to absence or presence of Nupr1, KIC mice develop tumors that phenocopy human classical- or QM-PDAC, respectively, thus becoming attractive models for preclinical drug trials. We investigated the impact of the homozygous deletion of the Nupr1 gene on pancreatic adenocarcinoma development and biology in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mouse model.
2012-12-16 | E-GEOD-42322 | biostudies-arrayexpress