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Transcriptional Profile Of Human Pancreatic Acinar Ductal Metaplasia

ABSTRACT: Transcriptional Profile Of Human Pancreatic Acinar Ductal Metaplasia

PROVIDER: PRJNA742923 | ENA |

REPOSITORIES: ENA

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Transcriptional Profile Of Human Pancreatic Acinar Ductal Metaplasia

Project description:Aberrant acinar to ductal metaplasia (ADM), one of the earliest events involved in exocrine pancreatic cancer development, is typically studied using pancreata from transgenic mouse models. We used primary, human pancreatic acinar cells to evaluate the transcriptional profile during the course of ADM.

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PHARMACOLOGICAL INHIBITION AND REVERSAL OF PANCREATIC ACINAR DUCTAL METAPLASIA

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Transcriptional profiling of pancreatic acinar to ductal metaplasia using laser capture microdissection

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease when diagnosed at a late stage, however patient survivorship significantly increases when the disease is detect prior to metastasis. To study the earliest events leading to PDAC initiation, we developed a genetically engineered mouse model of PDAC utilizing a tamoxifen-inducible Cre Recombinase knocked into the transcription factor Ptf1a locus to induce expression of oncogenic KrasG12D and Trp53R270H alleles in adult pancreatic acinar cells. Mice of the genotype KrasLSL-G12D/+; Trp53LSL-R270H/+; Ptf1aCreERTM/+ (KPT) developed PDAC following tamoxifen injection while control Cre recombinase negative KrasLSL-G12D/+; Trp53LSL-R270H/+; (KP) mice injected with tamoxifen did not develop PDAC. Acinar cells comprising the pancreata of tamoxifen treated KPT mice we observed to undergo acinar to ductal metaplasia (ADM), and formed precancerous lesions. We used laser capture microdissection (LCM) and RNA sequencing to generate, to our knowledge, the first transcriptional profile of an enriched population of metaplastic acinar cells in situ. Comparing the transcriptional profile of metaplastic acinar cells with the transcriptional profile of healthy pancreatic tissue identified differentially expressed genes associated with ADM. Ingenuity pathway analysis revealed transcriptional regulators and canonical signaling pathways involved in ADM. LCM was used to generate a transactional profile of cancer cells isolated from pancreatic tumors, and differential gene expression analysis revealed a subset of genes which are overexpressed in both ADM and PDAC relative to healthy pancreas. Further analysis of genes expressed in both pancreatic cancer precursor ADM lesions and invasive PDAC may lead to the identification of novel biomarkers of PDAC.

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ST6Gal1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression

Project description:This study describes a novel function for the ST6GAL1 sialyltransferase in promoting acinar to ductal metaplasia (ADM). ST6GAL1 activity facilitates ADM by reprogramming acinar cells into a more progenitor-like state.

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Project description:Oncogenic KrasG12D, a driver mutation of pancreatic ductal adenocarcinoma (PDAC), induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). Here, we show that both functional complexes of mTOR (mechanistic target of rapamycin kinase, mTORC1 and mTORC2) are specifically activated in ADM. Murine models uncover that mTORC1 and mTORC2 cooperate to promote KrasG12D-driven ADM development. Proteomic analyses identify Arp2/3 complex, an actin nucleator, as the common downstream effector: mTORC1 is responsible for the protein synthesis of Rac1 and Arp3 while mTORC2 promotes the Arp2/3 complex activity via Akt/Rac1 signalling. Genetic ablation of Arp2/3 complex completely arrests KrasG12D-driven ADM development. The Arp2/3 complex-mediated y-branching of actin network promotes the basolateral spread of filamentous actin, which is indispensable for acinar cells-initiated carcinogenesis. Induced by oncogenic KrasG12D, ADM is a metaplastic phenotype of acinar cells that requires extensive actin rearrangements. mTORC1 and mTORC2, downstream targets of KrasG12D, have well-established oncogenic functions in PDAC development. The actin-related protein 2/3 (Arp2/3) complex is the first identified actin nucleator. Regarded as textbook knowledge, it is activated by EGFR/Rac1 signalling to promote the polymerisation of branched actin filaments from pre-existing filaments in numerous biological contexts. Hereby, we identify that mTORC1 and mTORC2 attain a dual, yet non-redundant, regulatory role in promoting Arp2/3 complex function, which is responsible for generating basolateral filamentous actin in ADM. Thus, the role of Arp2/3 complex fills up the missing gap between putative oncogenic signals and actin dynamics underlying PDAC initiation.

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Project description:Transcriptional profiling of pancreatic acinar to ductal metaplasia using laser capture microdissection

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