A single-cell atlas of the tumor, stromal and immune microenvironments in pancreatic cancer liver metastasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197177 | GEO | 2023/04/20
REPOSITORIES: GEO
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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 cancer is a devastating disease with both local invasion and distant metastasis. Identifying the genes expressed in liver metastases and signatures of metastatic progression would therefore be of particular importance as they could aid in both recurrence prediction as well as representing novel therapeutic targets. Keywords: Gene expression profiling We have performed microarray gene expression analysis of normal pancreas, primary pancreatic ductal adenocarcinoma (PDAC), normal liver and pancreatic liver metastases to identify potential therapeutic targets.
2013-08-15 | E-GEOD-19280 | biostudies-arrayexpress
Project description:Pancreatic cancer is a devastating disease with both local invasion and distant metastasis. Identifying the genes expressed in liver metastases and signatures of metastatic progression would therefore be of particular importance as they could aid in both recurrence prediction as well as representing novel therapeutic targets. Keywords: Gene expression profiling We have performed microarray gene expression analysis of normal pancreas, primary pancreatic ductal adenocarcinoma (PDAC), normal liver, and pancreatic liver metastases to identify potential therapeutic targets. This dataset is part of the TransQST collection.
2013-08-15 | E-GEOD-19279 | biostudies-arrayexpress
Project description:Uncontrolled growth, distant metastasis and chemoresistance are critical characteristics of pancreatic ductal adenocarcinoma (PDAC). We identified PCDH1 acting as a novel prognostic marker for PDAC. PCDH1 enhanced p65 nuclear localization by interacting with KPNB1, therefore activates NF-κB signaling pathway and function during the progression of PDAC.
2022-07-20 | GSE201971 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer in which differences in survival rates might be related to a variety in gene expression profiles. Although the molecular biology of PDAC begins to be revealed, genes or pathways that specifically drive tumour progression or metastasis are not well understood. Therefore, we performed microarray analyses on whole-tumour samples of 2 human PDAC subpopulations with similar clinicopathological features, but extremely distinct survival rates after potentially curative surgery, i.e., good outcome (OS and DFSM-bM-^@M-^I>M-bM-^@M-^I50M-bM-^@M-^Imonths) versus bad outcome (OSM-bM-^@M-^I<M-bM-^@M-^I19M-bM-^@M-^Imonths and DFSM-bM-^@M-^I<M-bM-^@M-^I7M-bM-^@M-^Imonths). Additionally, liver- and peritoneal metastases were analysed and compared to primary cancer tissue. The integrin and ephrin receptor families were upregulated in all PDAC samples, irrespective of outcome, supporting an important role of the interaction between pancreatic cancer cells and the surrounding desmoplastic reaction in tumorigenesis and cancer progression. Moreover, some components, such as ITGB1 and EPHA2, were upregulated in PDAC samples with a poor outcome, Additionally, overexpression of the non-canonical Wnt/M-NM-2-catenin pathway and EMT genes in PDAC samples with bad versus good outcome suggests their contribution to the invasiveness of pancreatic cancer, with M-NM-2-catenin being also highly upregulated in metastatic tissue. Thus, we conclude that components of the integrin and ephrin pathways and EMT-related genes might serve as molecular markers in pancreatic cancer as their expression seems to be related with prognosis. Microarray analysis was performed on 'Good' and 'Bad' patient samples (samples with similar pathological characteristics were chosen based on the definition of the 2 diverse survival outcome groups and the required RIN values above 7.1), on surrounding non-tumoural pancreatic control samples, liver metastasis (LM) and peritoneal metastasis (PM). Comparisons between good vs. control, bad vs. control, good vs. bad, and primary pancreatic cancer versus metastasis were performed.
2013-01-09 | E-GEOD-42952 | biostudies-arrayexpress
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:Pancreatic adenocarcinoma (PDAC) is an extremely deadly disease for which all treatments available have failed to improve life expectancy significantly. This may be explained by the high metastatic potential of PDAC cells, which results from their physiological dedifferentiation towards a mesenchymal phenotype. Some PDAC present cell-in-cell structures but their origin and significance is currently unknown. We show here that cell-incells form after cell cannibalism. We found PDAC patients whose tumors display cell cannibalism develop less metastasis than those without. In vitro, cell cannibalism was enhanced by the TGFβ and repressed by the Nuclear protein (Nupr)1, and was coupled to a defective epithelial-to-mesenchymal transition of PDAC cells. Cannibalism ends with death of PDAC cells, consistent with a metastasis suppressor role for this phenomenon. Hence, our data indicates a protective role for cell cannibalism in PDAC and identifies Nupr1 and TGFβ as molecular regulators of this process.
2012-06-18 | GSE38772 | GEO
Project description:Metastasis is a multistage process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and colonize these foreign tissue environments. Each of these processes involves rate-limiting steps that are influenced by stromal cells of the tumor microenvironment. While the tumor microenvironment has emerged as a major regulator of cancer progression in other organ sites, our knowledge of the brain metastatic microenvironment is currently very limited. Thus, we aim to dissect signatures of tumor-stroma interactions in brain metastasis in order to identify factors that regulate the homing, seeding and outgrowth of cancer cells in this highly specialized microenvironment. We took advantage of an experimental metastasis model in which variants of the human breast cancer line MDA-MB-231 home to the brain in xenografted animals. To simultaneously capture gene expression changes in the tumor and stromal compartment, we used a dual species-specific microarray platform, the HuMuProtIn array, to discriminate between differentially expressed protease or protease inhibitor genes of human (tumor) or murine (stromal) origin. RNA was isolated from early and late brain, bone and lung metastases from xenograft models of breast metastasis. RNA was also isolated from non-tumor-burdened mouse brain, bone and lung as normal tissue controls. RNA from tissue homing cell lines was isolated in vitro to serve as a control for the human-derived RNA. Samples were collected from 24 total tumor-burdened mice, with 3 replicates for each condition and control. A total of 36 samples are included here.
2014-07-04 | E-GEOD-47930 | biostudies-arrayexpress
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