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A decision point between transdifferentiation and programmed cell death priming controls

ABSTRACT: The involvement of cell death pathways in the early stage of pancreatic ductal adenocarcinoma (PDAC) development, especially KRAS-dependent acinar-to-ductal metaplasia (ADM), remains to be investigated. Here, we show that TAK1 mediates cell survival during ADM transdifferentiation through suppression of Caspase-8/3-dependent apoptosis and RIPK3-MLKL-dependent necroptosis, which could be targeted for prevention and treatment of PDAC. Given that mutations are a driving force of PDAC development and TAK1 might modulate chromosomal stability and the mutational spectrum of PDAC via NF-κB, we performed an array comparative genomic hybridization (aCGH) analysis on pancreatic tissue of five KRASG12D TAK1/CASP8ΔAc RIPK3-/- mice and five KRASG12D mice. Interestingly, both genotypes showed distinct chromosomal abnormalities with gain or loss of genetic regions. Further analysis of these chromosomal regions showed they contained genes known to be involved in the pathogenesis of human PDAC, such as Trp53, Cdkn2a, Smad4, Rnf43 and Arid1a. However, we did not observe a consistent pattern of chromosomal/gene alterations in the majority of samples/tumors between KRASG12D single transgenic mice and KRASG12D TAK1/CASP8ΔAc RIPK3-/- mice, arguing against the hypothesis that TAK1 deficiency mediated late stages of tumor promotion through changes in chromosomal stability.

ORGANISM(S): Mus musculus

PROVIDER: GSE282891 | GEO | 2024/11/26

REPOSITORIES: GEO

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A decision-point between programmed cell death and transdifferentiation in pancreatic cancer

Project description:Transdifferentiation and changes of cellular identity are hallmarks of malignant transformation1-3. As such, the process of acinar-to-ductal metaplasia (ADM) represents a fundamental step in pancreatic ductal adenocarcinoma (PDAC) development, but regulatory pathways controlling ADM are not fully understood4,5. Here, we show that murine pancreatic acinar cells upregulate expression of CASPASE3, CASPASE8, RIPK3 and MLKL - key molecules driving both apoptosis and necroptosis6,7 - during transdifferentiation towards a duct-like phenotype. Spontaneous activation of these respective programmed cell death (PCD) pathways during KRAS-driven transdifferentiation is counterbalanced by transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase transmitting inhibitory phosphorylation signals towards the apoptosis- and necroptosis activator RIPK18. Genetic deletion or pharmacological inhibition of TAK1 simultaneously triggered apoptosis and necroptosis and thereby prevented KRAS-driven ADM in vitro as well as KRAS-driven PDAC in vivo. In line, TAK1 expression is upregulated in human PDAC cells, and pharmacological inhibition of TAK1 triggered PCD in organoid and spheroid cells derived from PDAC patients. Collectively, these findings suggest that TAK1 defines a decision point between ADM and PCD in pancreas cells and represents a promising pharmacological target for the prevention and treatment of PDAC patients.

2024-11-29 | GSE223135 | GEO

mTORC1 and mTORC2 converge on the Arp2/3 complex to promote KrasG12D-induced acinar-to-ductal metaplasia and early pancreatic carcinogenesis

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.

2021-01-07 | PXD018296 | Pride

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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Project description:To determine the molecular basis of gene regulation in pancreatic ductal epithelial cells, we developed methods for the isolation of this cell population during mouse development and normal adult homeostasis, as well as in conditions with ductal features (acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC)). Our technique utilizes the specificity of Dolichos biflorus Agglutinin (DBA) lectin marking the entire normal ductal tree, including terminal intercalated ducts (putative sites of stem or progenitor cells) and ductal structures in ADM and PanIN. We used ferromagnetic-labeled DBA lectin to isolate ductal structures. Ductal cells were isolated under the following conditions: (1) Embryonic Development in wild type mice: E14.5, E15.5, E16.5, and postnatal day 1 (P1); (2) Injury and regeneration (pancreatitis) 0, 1, 3, 5 days following cerulein-induced acute pancreatitis. Cerulein is a cholecystokinin analog which produces a self-limited pancreatitis with injury and subsequent regeneration and repair, completed five days after insult; and (3) Pdx1-Cre;LSL-KrasG12D/+ mice aged 10 and 20 weeks that harbor PanIN lesions and a subset develop PDAC. Ductal/PanIN cells were isolated from these mice and appropriate control mice (Pdx1-Cre;Kras+/+).

2015-09-30 | GSE40895 | GEO

Inactivation of the Euchromatic Histone-lysine N-methyltransferase 2 Pathway in Pancreatic Epithelial Cells Antagonizes Cancer Initiation and Pancreatitis-Associated Promotion by Altering Growth and Immune Gene Expression Networks

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2021-07-01 | GSE169525 | GEO

Digital spatial profiling of pancreatic ductal adenocarcinoma, acinar ductal metaplasia and adjacent normal pancreas tissue

Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most important histological subtype of pancreatic cancer, accounting for approximately 90% of all pancreatic cancers.Acinar to ductal metaplasia (ADM) is a recently recognized, yet less well-studied, precursor lesion of PDAC developed in the setting of chronic pancreatitis. Through digital spatial mRNA profiling, we compared ADM and adjacent PDAC tissues from patient samples to unveil the bridging genes, bridging signaling pathway and bridging molecular function during the malignant transformation of pancreatitis.

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Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [snATAC]

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Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [RNA-seq]

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Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [CUT&RUN]

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Project description:Inflammatory transcription networks have been linked with the development of pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrate that NFATc1 is both necessary and sufficient to drive progression of KrasG12D-initiated PDAC, particularly in the context of inflammation. Significantly, nuclear NFATc1 accelerates PDAC development in KrasG12D mice, whereas conditional NFATc1 deletion or pharmacological inhibition attenuates inflammation-mediated carcinogenesis. Mechanistically, NFATc1 induces STAT3 expression, complex formation and signal integration in PDAC. Genome-wide ChIP-sequencing and expression analysis in cells derived from c.n.NFATc1;KrasG12D mice identified combinatorial NFATc1/STAT3 binding at chromatin enhancer sites and subsequent regulation of key molecules involved in oncogenic signaling, growth and inflammation. Together, this study supports the relevance of inflammatory transcription factor networks in pancreatic carcinogenesis and provides a theoretical platform for therapeutic targeting of NFATc1 nucleoprotein complexes in PDAC. NFATc1 ChIP followed by high throughput sequencing in primary murine pancreatic cancer cells (referred to as NKC cells) derived from transgenic mice with pancreas-specific constitutive activation of NFATc1 and KrasG12D mutation in the presence or absence of STAT3 shRNA; 2 ChIP samples (scramble DNA and shSTAT3 DNA) and 1 unenriched input control from the same chromatin pool.

2014-06-30 | E-GEOD-39969 | biostudies-arrayexpress

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