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Effects of EZH2 ablation on promoter accessibility in mouse PDAC lines derived from KrasG12D/PEC/IkkαΔPEC tumors

ABSTRACT: We analyzed chromatin accessibility genome wide in EZH2KO and control cells derived from PDAC tumors of KrasG12D/PEC-IkkαΔPEC PDAC model mice to gain insight how the ablation of EZH2 affects the accessibility of genes involved in PDAC tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE148335 | GEO | 2021/12/31

REPOSITORIES: GEO

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Effects of EZH2 ablation on promoter accessibility in mouse PDAC lines derived from KrasG12D/PEC/IkkαΔPEC tumors

Project description:Effects of EZH2 ablation on promoter accessibility in mouse PDAC lines derived from KrasG12D/PEC/IkkαΔPEC tumors

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Next Generation Sequencing Quantitative Analysis of altered expression of genes in KRASG12D PDAC tissues

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EZH2 deletion does not impact acinar cell regeneration but restricts progression to pancreatic cancer in mice [ChIP-seq]

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Project description:Hierarchical clustering of pancreatic cancer cell lines based on differentially regulated genes between mesenchymal and epithelial PDAC cells derived from primary tumours and metastases from KrasG12D-driven mouse models of pancreatic cancer.

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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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Nuclear protein (Nupr)-1 is required for pancreatic adenocarcinoma development in Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl mice

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.

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