A decision-point between programmed cell death and transdifferentiation in pancreatic cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA925118 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23108228_1.fastq.gz | Fastqsanger.gz | |||
| SRR23108228_2.fastq.gz | Fastqsanger.gz | |||
| SRR23108229_1.fastq.gz | Fastqsanger.gz | |||
| SRR23108229_2.fastq.gz | Fastqsanger.gz | |||
| SRR23108230_1.fastq.gz | Fastqsanger.gz |
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Project description:A decision point between transdifferentiation and programmed cell death priming controls
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Project description:A decision-point between programmed cell death and transdifferentiation in pancreatic cancer
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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
Project description: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.
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Project description:Mecanism of action of TAK inhibitor on immune cells and cancer cells extracted from pancreatic tumor (PDAC)
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Project description:This is a multicenter observational study aimed to describe the efficacy and safety of regorafenib plus programmed cell death-1 (PD-1) inhibitors in Chinese patients with advanced colorectal cancer in routine clinical practice. The primary end point is overall survival. The secondary endpoints include progression-free survival, objective response rate, disease control rate and the incidence of treatment-related adverse events.
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Project description:Sex determination in mammals hinges on a cell fate decision in the fetal bipotential gonad between male Sertoli cells and female granulosa cells. While this decision normally is permanent, loss of key cell fate regulators such as the transcription factors Dmrt1 and Foxl2 can cause postnatal transdifferentiation from Sertoli to granulosa-like or vice versa. Here we examine the mechanism of transdifferentiation in mice carrying either a null mutation of Dmrt1 or a point mutation, R111G, that alters the DNA binding motif and causes human XY gonadal dysgenesis and sex reversal. We first define genes misexpressed during transdifferentiation and then show that female transcriptional regulators driving transdifferentiation in the mutant XY gonad (ESR2, LRH1, FOXL2) bind chromatin sites related to those normally bound in the XX ovary. We then define gene expression changes at the onset of transdifferentiation and abnormal chromatin compartments that may help destabilize cell fate and initiate transdifferentiation. We model the R111G mutation in mice and show that it causes dominant gonadal dysgenesis, analogous to its human phenotype but less severe. We show that R111G partially feminizes the testicular transcriptome and causes dominant disruption of DMRT1 binding specificity in vivo. These data help illuminate how transdifferentiation occurs when sexual cell fate maintenance is disrupted and identify chromatin sites and transcripts that may play key roles in the transdifferentiation process.
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Project description:Extraembryonic gut endoderm cells undergo programmed cell death during development
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Project description:The microbial loop is the conventional model by which nutrients and minerals are recycled in aquatic eco-systems. Biochemical pathways in different organisms become metabolically inter-connected such that nutrients are utilized, processed, released and re-utilized by others. The result is that unrelated individuals end up impacting each others’ fitness directly through their metabolic activities. This study focused on the impact of programmed cell death (PCD) on a population’s growth as well as its role in the exchange of carbon between two naturally co-occurring halophilic organisms. Flow cytometric, biochemical, 14C radioisotope tracing assays, and global transcriptomic analyses show that organic algal photosynthate released by Dunalliela salina cells undergoing PCD complements the nutritional needs of other non-PCD D. salina cells. This occurs in vitro in a carbon limited environment and enhances the growth of the population. In addition, a co-occurring heterotroph Halobacterium salinarum re-mineralizes the carbon providing elemental nutrients for the mixoheterotrophic chlorophyte. The significance of this is uncertain and the archaeon can also subsist entirely on the lysate of apoptotic algae. PCD is now well established in unicellular organisms; however its ecological relevance has been difficult to decipher. In this study we found that PCD in D. salina causes the release of organic nutrients such as glycerol, which can be used by others in the population as well as a co-occurring halophilic archaeon. H. salinarum also re-mineralizes the dissolved material promoting algal growth. PCD in D. salina was the mechanism for the flow of dissolved photosynthate between unrelated organisms. Ironically, programmed death plays a central role in an organism’s own population growth and in the exchange of nutrients in the microbial loop. Halobacterium NRC-1 was grown to mid-logarithmic phase (OD600 ~0.4 – 0.8) in MM2. Cells were harvested and washed in MM1 and incubated in MM1 (control) or in Dunaliella harvested supernatant. Cells were harvested at time zero, 5, 10, 20, 40, 80, 160 minutes. RNA from two biological replicate time courses were prepared, averages of these replicates are reported in the published study. The zero time point was harvested immediately after incubation Halobacteria-NRC1 in MM1 or in Dunaliella salina's supernatant.
2013-05-08 | E-GEOD-45752 | biostudies-arrayexpress
Project description:We have published results demonstrating that UV-C induces apoptotic-like changes in Arabidopsis (Danon and Gallois FEBS lett (1998) 437: 131-136). The Programmed Cell Death "phenotype" of nucleus shape, DNA laddering caspase-like activity is similar to what has been described in other plant PCD. This demonstrates that UV-C is an appropriate and controllable trigger to study PCD in plants. Using selected mutants and a set of chosen conditions we are aiming at identifying genes that are part of the PCD pathways in plants and filter out the general stress response. We are asking for a medium size experiment knowing that additional microarray analysis are likely to be required to refine the results obtained. We are currently awaiting the results of Affymetrix RNAs hybridisation of PCD-induced wild type that will define the appropriate single time point of the proposed analysis. The rationale is to vary treatments in order to distinguish changes in gene transcription arising from general cellular stress responses to the trigger used from those specific to PCD: 1. We will use wild-type Arabidopsis seedlings as a negative control to provide the basal gene expression pattern. 2. A dose of UV-C radiation of 1KJ/m2. We will irradiate wild type with this non PCD-inducing dose of UV-C radiation to identify sets of genes that respond to UV-induced damage but whose expression is not linked to cell death. 3. A dose of UV-C radiation of 50 KJ/m2. We will irradiate wild type with a PCD-inducing dose of UV-C radiation to identify sets of genes that respond to UV-induced damage and cell death. 4. We have shown that the cell death induced by UV is light dependant, the control, sub-inducing dose and inducing dose treatments will be repeated and the plants kept in the dark until RNA sampling. In those conditions there is no PCD.
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