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: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:The liver is the major site of metastasis for pancreatic ductal adenocarcinoma (PDAC). In this work, we describe a mechanism wherein serine sythensis is essential for PDAC liver metastasis. To describe this, we knocked out Phgdh in mouse KPC cells and then co-cultured the cells with mouse hepatocytes.
2026-07-01 | GSE324743 | GEO
Project description:Alternatively spliced tissue factor (asTF) promotes progression of pancreatic ductal adenocarcinoma (PDAC) by activating beta1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class, humanized, inhibitory, anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Study results. When administered alone, hRabMab1 achieved only marginal penetration of experimental tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNAseq analysis of primary tumors showed that the addition of hRabMab1 to gem/paclitaxel enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. Conclusions. This study demonstrates that hRabMab1 may help suppress metastasis in PDAC.
2024-12-31 | GSE252286 | 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:Liver metastases are frequent and challenging to treat as the liver is a metabolically highly active and immune-tolerant organ. However, how cancer cells exploit the nutrients available in the liver to further exacerbate evasion from the immune system remains largely unknown. We discovered that palmitate availability in the liver promotes neutrophil extracellular traps (NETs) in the presence of cancer cells. Mechanistically, we found that liver metastases from breast and colorectal cancer require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to secrete laminin-511. In turn, neutrophils in the liver metastasis environment responded to laminin-511 by increasing NETosis and decreasing their cancer cell killing capacity. In line, we observed that silencing ZDHHC17 in cancer cells decreased metastasis growth only in the presence of neutrophils, while metastasis growth was rescued in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we found that liver palmitate not only aids cancer cell intrinsic processes but it also enables cancer cells to evade neutrophil destruction.
2026-06-29 | GSE300657 | GEO
Project description:Liver metastases are frequent and challenging to treat as the liver is a metabolically highly active and immune-tolerant organ. However, how cancer cells exploit the nutrients available in the liver to further exacerbate evasion from the immune system remains largely unknown. We discovered that palmitate availability in the liver promotes neutrophil extracellular traps (NETs) in the presence of cancer cells. Mechanistically, we found that liver metastases from breast and colorectal cancer require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to secrete laminin-511. In turn, neutrophils in the liver metastasis environment responded to laminin-511 by increasing NETosis and decreasing their cancer cell killing capacity. In line, we observed that silencing ZDHHC17 in cancer cells decreased metastasis growth only in the presence of neutrophils, while metastasis growth was rescued in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we found that liver palmitate not only aids cancer cell intrinsic processes but it also enables cancer cells to evade neutrophil destruction.
2026-06-29 | GSE300660 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastatic dissemination and poor clinical outcomes. Although SMAD4 is frequently altered in PDAC, the majority of tumors retain wild-type SMAD4, which paradoxically acquires pro-metastatic functions during disease progression. How SMAD4 transcriptional output is reprogrammed to support metastasis in advanced PDAC remains poorly understood.Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical modifier that promotes a metastasis-promoting transcriptional state of SMAD4. PRMT1 catalyzes asymmetric dimethylation of SMAD4 at arginine 272 (R272), a modification that does not alter SMAD4 expression but stabilizes nuclear SMAD2/3-SMAD4 complexes and redirects SMAD4 chromatin engagement toward epithelial-mesenchymal transition (EMT) gene programs. Mechanistically, R272-methylated SMAD4 promotes the recruitment of a BRG1-CTCF transcriptional complex, enabling chromatin-dependent activation of pro-metastatic transcriptional outputs.Importantly, pharmacological inhibition of PRMT1, particularly in combination with BRG1 degradation, dismantles methylation-dependent SMAD4 transcriptional complexes, suppresses EMT programs, and markedly reduces liver metastasis in preclinical PDAC models.Together, these findings uncover a post-translational mechanism that governs SMAD4 transcriptional specificity and identify PRMT1-dependent methylation as a therapeutic vulnerability in SMAD4-wild-type pancreatic cancer.
2026-07-16 | GSE338354 | GEO
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:In previous studies, we found that high expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3) was associated with more lymph node metastases in pancreatic ductal adenocarcinoma (PDAC). We here report in PDAC Aldh1a3 promotes lung colonization, while is dispensable in liver colonization or proliferation. Aldh1a3 upregulates the transcription of Plxnb1 and Nrp1 via accelerating acetylation at histone H3 lysine in the promoter regions of Plxnb1 and Nrp1. The enhancing signaling of Sema4d-Plxnb1 and Sema3a-Nrp1 between pancreatic cancer cells and lung epithelial cells facilitate tumor cells to colonize in the lung. Our studies have uncovered Aldh1a3 as a key regulator of semaphorin signaling. Sema4d-Plxnb1 and Sema3a-Nrp1 signaling is important for lung metastatic organotropism of PDAC, but is dispensable in liver metastasis.
2026-03-02 | GSE248375 | GEO