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Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia.

ABSTRACT: Primary cilia have been proposed to participate in the modulation of growth factor signaling pathways. In this study, we determined that ciliogenesis is suppressed in both pancreatic cancer cells and pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreatic ductal adenocarcinoma (PDAC). Primary cilia were absent in these cells even when not actively proliferating. Cilia were also absent from mouse PanIN cells in three different mouse models of PDAC driven by an endogenous oncogenic Kras allele. Inhibition of Kras effector pathways restored ciliogenesis in a mouse pancreatic cancer cell line, raising the possibility that ciliogenesis may be actively repressed by oncogenic Kras. By contrast, normal duct, islet, and centroacinar cells retained primary cilia in both human and mouse pancreata. Thus, arrested ciliogenesis is a cardinal feature of PDAC and its precursor PanIN lesions, does not require ongoing proliferation, and could potentially be targeted pharmacologically.

SUBMITTER: Seeley ES

PROVIDER: S-EPMC2629528 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia.

Seeley E Scott ES Carrière Catherine C Goetze Tobias T Longnecker Daniel S DS Korc Murray M

Cancer research 20090101 2

Primary cilia have been proposed to participate in the modulation of growth factor signaling pathways. In this study, we determined that ciliogenesis is suppressed in both pancreatic cancer cells and pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreatic ductal adenocarcinoma (PDAC). Primary cilia were absent in these cells even when not actively proliferating. Cilia were also absent from mouse PanIN cells in three different mouse models of PDAC driven by an endogenous oncogeni ...[more]

PMID: 19147554

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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 in humans 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. Here, we performed laser-capture microdissection on surgically resected specimens from 18 patients to isolate, with high purity, DNA for whole-genome bisulfite sequencing from four relevant cell types: acini, nonneoplastic ducts, PanIN lesions, and PDAC lesions. Differentially methylated regions (DMR) were identified using two complementary analytical approaches: bsseq, which identifies any DMRs but is particularly useful for large block-like DMRs, and informME, which profiles the potential energy landscape across the genome and is particularly useful for identifying differential methylation entropy. Both global methylation profiles and block DMRs clearly implicated an acinar origin for PanINs. At the gene level, PanIN lesions exhibited an intermediate acinar-ductal phenotype resembling acinar-to-ductal metaplasia. In 97.6% of PanIN-specific DMRs, PanIN lesions had an intermediate methylation level between normal and PDAC, which suggests from an information theory perspective that PanIN lesions are epigenetically primed to progress to PDAC. Thus, epigenomic analysis complements histopathology to define molecular progression toward PDAC. The shared epigenetic lineage between PanIN and PDAC lesions could provide an opportunity for prevention by targeting aberrantly methylated progression-related genes.SignificanceAnalysis of DNA methylation landscapes provides insights into the cell-of-origin of PanIN lesions, clarifies the role of PanIN lesions as metaplastic precursors to human PDAC, and suggests potential targets for chemoprevention.

Project description:BackgroundWith 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 findingsWe 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.ConclusionsOur 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.

Dataset Information

Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia.

Publications

Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia.

Similar Datasets

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