Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of mouse Pancreatic Intraepithelial Neoplasias (PanINs) with NF-κB Essential Modulator (NEMO) knockout against NEMO wild-type

ABSTRACT: The canonical NF-κB pathway is active in 70% of all pancreatic cancer cases and NF-κB Essential Modulator (NEMO) is essential for the activation of this pathway. In our study, we used KC mice, which express the oncogenic KRAS and develop precancerous lesions termed Pancreatic Intraepithelial Neoplasias (PanINs), and KNeC mice, which express the oncogenic KRAS and have NEMO deleted in their pancreatic cells. These mice were injected with cerulein to promote the development of pancreatitis (cerulein dosage= 50μg/kg). Cerulein was injected at 8 hourly intervals for 2 days in total. The first injection day was when mice reached their sixth week of age and the second injection day was 3 days after the first injection day. Both KC and KNeC mice developed PanINs. At the age of 10 months, pancreata of KC and KNeC mice were analyzed. Using laser capture microdissection, PanINs from both groups were excised and their transcriptome was analyzed though RNA-seq.

INSTRUMENT(S): RNeasy Micro Kit (QIAGEN #74004), DNBSEQ-G400, PALM Microbeam Rel. 4.9 with RoboMover microscope (Zeiss), NuGEN Trio low input RNA-seq

ORGANISM(S): Mus musculus

SUBMITTER: Miltiadis Tsesmelis

PROVIDER: E-MTAB-12433 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

Dataset Information

RNA-seq of mouse Pancreatic Intraepithelial Neoplasias (PanINs) with NF-κB Essential Modulator (NEMO) knockout against NEMO wild-type

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