Ontology highlight
ABSTRACT:
PROVIDER: PRJNA664673 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12777500_1.fastq.gz | Fastqsanger.gz | |||
| SRR12777500_2.fastq.gz | Fastqsanger.gz | |||
| SRR12777501_1.fastq.gz | Fastqsanger.gz | |||
| SRR12777501_2.fastq.gz | Fastqsanger.gz | |||
| SRR12777502_1.fastq.gz | Fastqsanger.gz |
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Project description:Background Pancreatic ductal adenocarcinoma (PDAC) tends to undergo distant metastasis, especially liver metastasis, leading to a poor prognosis. Metabolic remodelling and epigenetic reprogramming are two important hallmarks of malignant tumours and participate in regulating PDAC tumorigenesis and metastasis. However, the interaction between these two processes during PDAC metastasis has not been fully elucidated. Methods We performed metabolomics analysis to identify the critical metabolites associated with PDAC liver metastasis and focused on guanidinoacetic acid (GAA). Intracellular GAA content was significantly increased in liver metastatic PDAC cells compared to primary cancer cells in mouse xenograft tumour models. The effects of GAA supplementation and glycine amidinotransferase (GATM) knockdown on PDAC metastasis were assessed by analysing cell migration, filopodia formation, epithelial-mesenchymal transition (EMT), and in vivo metastasis in different cell and animal models. Next, ChIP‒qPCR, 3C‒qPCR, and CRISPRi/dCas9-KRAB experiments were used to validate the “epigenome-metabolome" mechanism. Finally, the results of in vitro approaches, including RNA-seq, CUT&RUN, RT‒qPCR, and western blot analyses, as well as luciferase reporter gene assay and transwell assay, revealed the GAA-c-Myc-HMGA axis and transcription-activating histone modifications reprogramming. Results A high level of intracellular GAA was associated with PDAC liver metastasis. GAA could promote the migration, EMT, and liver metastasis of pancreatic cancer cells in vitro and in vivo. Next, we explored the role of GATM-mediated de novo GAA synthesis in pancreatic cancer metastasis. High expression of GATM was positively correlated with advanced N stage in PDAC. Knockdown of GATM significantly reduced the intracellular level of GAA, suppressed EMT, and inhibited PDAC liver metastasis, and these effects were attenuated by GAA supplementation. Mechanistically, we identified the active enhancers looped to the GATM gene locus that promoted GATM expression and PDAC liver metastasis. Furthermore, we found that GAA promoted cell migration and EMT by regulating c-Myc-mediated high mobility group AT-hook protein expression. Moreover, GAA increased the H3K4me3 modification level by upregulating histone methyltransferases, which induced the transcription of metastasis-related genes, including MYC. Conclusions These findings revealed the critical role of the epigenome-metabolome interaction in regulating PDAC liver metastasis and suggested potential therapeutic strategies targeting GAA metabolism and epigenetic regulatory mechanisms.
2023-01-07 | GSE193268 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignant tumors all over the world, with a 5-year survival rate of less than 10%1,2. Usually diagnosed at an advanced stage, PDAC is highly resistant to current therapies, partly due to an extremely high rate of distant metastasis (>80%) at first diagnosis. The liver is the most frequent site of distant metastases for PDAC. Current therapeutic options for PDAC patients with liver metastasis are extremely limited3. Thus, understanding the molecular mechanisms underlying hepatic metastasis of PDAC is urgently needed to help us develop more effective treatments and improve survival for these patients with advanced disease.
2023-04-20 | GSE197177 | GEO
Project description:Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor progression and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) DOCK8 on lysosomes. Surprisingly, we found that DOCK8 is aberrantly expressed in a subset of PDAC where it promotes cell invasion and proliferation. Further, DOCK8 associates with lysosomes and regulates lysosomal morphology and motility. DOCK8 promotes actin polymerization at the surface of lysosomes, while increasing the levels and proteolytic activity of the lysosomal protease cathepsin B. Depletion of DOCK8 significantly reduces extracellular matrix degradation and impairs the invasive capacity of PDAC cells. Further, CRISPR-based knockout of DOCK8 dramatically reduces tumor size and metastasis in vivo. Together, these findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation, tumor progression, and metastasis.
2023-01-10 | MSV000091036 | MassIVE
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a high level of liver metastasis. Despite substantial advances, resistance to therapy, including gemcitabine, is still a major obstacle to improved progression free survival. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA-damaging therapy induced angiocrine factors and chemosensitivity in malignant cells. However, the effect of EC-FAK regulated angiocrine signalling in chemosensitivity of metastatic PDAC remains unexplored. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC reduces liver metastasis and improves survival rates in gemcitabine treated, but not untreated, mice, without affecting primary tumour growth, tumour vascularization, blood vessel leakage or early metastatic events. Phosphoproteomics analysis show a downregulation of the MAPK/ RAF/ PAK signalling pathways in gemcitabine treated FAK-depleted ECs compared to gemcitabine treated WT ECs. Moreover, low levels of EC-FAK correlate with increased survival and reduced relapse in gemcitabine treated human PDAC patients, supporting the clinical relevance of our findings. Altogether, we have identified a new role of EC-FAK regulating PDAC liver metastasis upon gemcitabine treatment that impacts on survival.
2023-03-10 | PXD021542 | Pride
Project description:Autophagy is activated in pancreatic ductal adenocarcinoma (PDAC) and is currently being considered a promising therapeutic target in clinical trials. PDAC is a highly lethal disease with incidence rate equalling mortality rate. Main reasons for PDAC lethality are late-stage diagnosis, high agressiveness and metastatic rate, lack of effective treatments as well as specific diagnostic markers. Here we show that varying levels of the Autophagy related gene 5 (Atg5) determine pancreatic tumor formation and malignancy. While homozygous deletion of Atg5 blocks tumor progression in an in vivo model of PDAC, heterozygous deletion increases tumor aggressiveness and metastasis. Further analyses reveal that monoallelic loss of Atg5 affects mitochondrial homeostasis, changes intracellular calcium oscillations, heightens extracellular cathepsin activities , and promotes a pro-tumorigenic inflammatory microenvironment collectively enhancing tumor cell migration, invasion, and metastasis. Future treatments should take into account that variations in the autophagy pathway may have opposing effects on pancreatic tumor load, especially considering the multitude of autophagy inhibitors currently tested in clinical trials.
2018-10-15 | E-MTAB-6275 | biostudies-arrayexpress
Project description:We used single cell RNA sequencing to investigate how macrophages regulate tumor-associated fibroblast heterogeneity in PDAC liver metastasis
2024-04-04 | GSE232335 | GEO
Project description:We used single cell RNA sequencing to investigate macrophage heterogeneity and their temporal and spatial distributions in PDAC liver metastasis
2023-12-11 | GSE215118 | GEO
Project description:The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor. We detected an upregulation of the secreted axon guidance molecule Netrin-1 (Ntn1) in human and mouse PDAC metastases that signals through its receptor, uncoordinated- 5b (Unc5b) to facilitate metastasis in vitro and in vivo. The mechanism of Ntn1 induction in liver metastasis is mediated by hepatic stellate cell (HSC) secreted retinoic acid through RXR/RAR and Elf3 signaling. Ntn1 is present in PDAC-derived extracellular vesicles (EVs) and facilitates metastasis by inducing HSC activation through both long and short distance intercellular communication. Importantly, administration of a neutralizing monoclonal NTN1 antibody decreased metastases and increased survival in several murine PDAC models (autochthonous and metastatic). Our studies reveal a new metabolic feed-forward loop for metastatic niche formation in the liver involving NTN1 in PDAC-secreted EVs and retinoic acid released from HSCs which is targetable using anti-NTN1 therapy.
2023-10-31 | GSE245306 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Prooncogenic secretome delivering and trafficking via exosomes is crucial for pre-metastatic microenvironment formation and metastasis. This study aims to explore the underlying molecular mechanisms of how PDAC derived exosomes (Pex) modulate the microenvironments of future sites of metastasis.So we dicided using Hepatic Stellate Cells to see their transcriptomes changing after Pex addition.
2021-04-30 | GSE148139 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Currently, there is no effective therapy to treat PDAC, and thus detailed molecular and functional evaluation of PDAC is needed to identify and develop better therapeutic strategies. Here we show that the transcription factor Kruppel-like factor 7 (KLF7) is overexpressed in PDAC and that inhibition of KLF7 blocks PDAC tumor growth and metastasis in cell culture and in mice. KLF7 expression in PDAC can be upregulated due to activation of a MAP kinase pathway or inactivation of the tumor suppressor p53, two alterations that occur in a large majority of PDACs. ShRNA-mediated knockdown of KLF7 inhibits the expression of interferon-stimulated genes (ISGs), which are necessary for KLF7-mediated PDAC tumor growth and metastasis. KLF7 knockdown also results in the downregulation of Discs Large MAGUK Scaffold Protein 3 (DLG3), resulting in Golgi complex fragmentation, and reduced protein glycosylation leading to reduced secretion of cancer-promoting growth factors such as chemokines. Genetic or pharmacological activation of Golgi complex fragmentation blocks PDAC growth and metastasis similar to KLF7 inhibition. Our results demonstrate a therapeutically amenable, KLF7-driven pathway that promotes PDAC growth and metastasis by activating ISGs and maintaining Golgi complex integrity.
2020-04-16 | GSE107184 | GEO