Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PRMT1-mediated arginine methylation redirects a metastasis-promoting transcriptional output of SMAD4 in pancreatic cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338354 | GEO | 2026/07/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

SMAD4 represses FOSL1 expression and pancreatic cancer metastatic colonization

Project description:Less than 8% of patients diagnosed with pancreatic ductal adenocarcinomas (PDAC) survive more than five years in part due to late stage diagnosis. Approximately half of PDAC patients exhibit loss of SMAD4, which correlates with increased metastatic disease. Here we demonstrate that SMAD4 is a suppressor of metastatic colonization. Using isogenic human PDAC cell lines expressing or lacking SMAD4, both in vitro and in vivo, we define SMAD4-dependent gene expression changes in metastatic lesions. We performed a pooled in vivo open reading frame (ORF) screen of SMAD4 transcriptional targets and identified genes that, induce tumor seeding and growth at secondary sites. We found that expression of the transcription factor FOSL1 was sufficient to drive metastatic colonization. SMAD4 directly binds and represses the activity of the FOSL1 enhancer. These studies demonstrate a direct role for SMAD4 in regulating metastatic colonization and identify FOSL1 as a SMAD4-regulated gene involved in PDAC progression.

2021-08-02 | GSE148248 | GEO

SMAD4-NFATc1 protein-protein interaction informed therapeutic vulnerability in SMAD4-deficient pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a median survival rate of approximately six months. While genetic profiling has uncovered common mutations in PDAC, developing targeted therapeutic strategies remains challenging. SMAD4 is frequently mutated or deleted in 30-55% of PDAC patients and correlates with poor survival rates. Such mutations frequently result in loss-of-function, thereby disrupting normal cell cycle regulation and contributing to tumorigenesis. Therefore, translating SMAD4 genotype into actionable targets are highly desired for therapeutic innovation in PDAC. In this study, we performed a SMAD4-focused oncogenic protein-protein interaction (oncoPPI) network mapping and revealed a direct physical interaction between SMAD4 and NFATc1. We found that SMAD4 interacts with NFATc1 in a TGF-independent and NFATc1 phosphorylation-dependent manner. Further, SMAD4 sequesters NFATc1 in cytoplasm and inhibits NFATc1 transcriptional activity. In PDAC cells, SMAD4-loss releases its inhibitory activity on NFATc1, activates NFATc1 transcriptional activity which drives STAT3 mRNA and protein upregulation. Pharmacological profiling identified multiple STAT3 inhibitors selectively inhibit the growth of SMAD4-loss PDAC cells. These results suggested a rewired SMAD4-NFATc1-STAT3 axis and targeting STAT3 as a potential therapeutic strategy in SMAD4-loss PDAC.

2026-02-02 | PXD067749 | Pride

PRMT1-dependent regulation of RNA metabolism and DNA damage response is a critical dependency in pancreatic ductal adenocarcinoma

Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, which represents a critical area of unmet need for novel therapeutic options. Here we deployed an RNAi-based in vivo functional genomics platform to identify epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this effort, we identified protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validated the role of PRMT1 in maintaining PDAC growth and informed the mechanism-of-action through proteomic and transcriptomic analyses. Mechanistically, we showed that inhibition of asymmetric arginine methylation globally impaired RNA metabolism, including RNA splicing, alternative polyadenylation, and transcription termination, causing a profound down-regulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, these data support PRMT1 as a compelling target in PDAC and inform a mechanism-based translational strategy for future therapeutic development.

2021-06-25 | GSE130242 | GEO

Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway

Project description:Brg1 is a subunit of SWI/SNF chromatin remodeling complex. To clarify the role of Brg1 for the progression and metastasis of pancreatic ductal adenocarcinoma (PDAC), we generated a PDAC mouse model with a dual recombinase system (Brg1 lox/lox; Pdx1-Flp; Kras FSF-G12D; Trp53 frt/frt; Rosa26 FSF-CreERT2) which enabled to ablate Brg1 in established PDAC with tamoxifen treatment. We established cancer cell lines derived from PDAC tumors developed in those mice and investigated the effect of Brg1 ablation on PDAC cell proliferation and metastasis. In order to determine the genes expression in Brg1-deleted mouse PDAC cells, we conducted a transcriptomic analysis using microarray using Brg1 wild type and Brg1-deleted mouse PDAC cells.

2022-04-30 | GSE199442 | GEO

Quantitative secretomics identifies ligand-receptor pairs in pancreatic cancer that mediate bidirectional crosstalk between cancer stem cells and nociceptors

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest and most metastatic cancers in human. PDACs respond poorly to therapies, partly due to cancer stem cells (CSCs) that self-renew, survive chemotherapies, metastasise and replenish the tumour. Factors secreted by tumour cells mediate autocrine/paracrine crosstalk with surrounding cells contributing to the stem cell niche but are still insufficiently characterised. Here we used quantitative SILAC proteomics to identify secreted factors enriched in CSC secretome compared to non-CSCs. Among them were GDF15 and VGF, factors involved in cachexia and pain stimuli. GDF15 and VGF promoted CSC self-renewal and growth through autocrine effects. TGFβ/Activin signalling lowered GDF15 and VGF expression via SMAD2/3-SMAD4-SNON, switching to ATF4-CREB-mediated induction upon cell stress. Co-culture of PDAC-CSCs and hESC-derived neural cells for mimicking cellular crosstalk in PDAC revealed that paracrine signalling via GDF15/VGF promoted nociceptor formation and neurite outgrowth. In turn, Substance P from neurons supported CSC self-renewal, EMT/migration and clonal evolution that was also impacted by SMAD4 genetic status. Lastly, the serum levels of GDF15 and VGF were elevated in PDAC patients suggesting their utility as biomarkers for PDAC detection. Collectively, our data uncovered that cachexia and pain signalling factors mediate the crosstalk between CSCs and nociceptors.

2024-04-06 | PXD046026 | Pride

Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity

Project description:Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to- mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

2025-04-10 | GSE287625 | GEO

Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway (ChIP-seq)

Project description:Brg1 is a subunit of SWI/SNF chromatin remodeling complex. To clarify the role of Brg1 for the progression and metastasis of pancreatic ductal adenocarcinoma (PDAC), we generated a PDAC mouse model with a dual recombinase system (Brg1 lox/lox; Pdx1-Flp; Kras FSF-G12D; Trp53 frt/frt; Rosa26 FSF-CreERT2) which enabled to ablate Brg1 in established PDAC with tamoxifen treatment. We established cancer cell lines derived from PDAC tumors developed in those mice and investigated the effect of Brg1 ablation on PDAC cell proliferation and metastasis. In order to determine the genes that Brg1 directly regulates, we conducted a chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) analysis for Brg1 and histone modifications (H3K27ac and H3K27me3) using Brg1 wild type and Brg1-deleted mouse PDAC cells.

2022-04-30 | GSE199610 | GEO

Multi-omics of colon tumor progression organoids reveals putative mediators of colorectal cancer metastasis

Project description:The development of metastasis severely reduces the life expectancy of patients with colorectal cancer (CRC). Loss of SMAD4 is a key event in late-stage CRC resulting in the progression to metastatic CRC in 10-30% of the cases. However, the biological processes and underlying molecular mechanisms that it affects are not fully understood. Here, we applied a multi-omics approach to a CRC tumor progression organoid model that faithfully reflects the metastasis-inducing effects of SMAD4 inactivation. We show that loss of SMAD4 results in loss of differentiation and activation of pro-migratory and cell proliferation processes, which is accompanied by the disruption of several key oncogenic pathways, including the TGFB, WNT, and VEGF pathways. In addition, SMAD4 inactivation leads to increased secretion of proteins that are known to be involved in a variety of pro-metastatic processes. Finally, we show that one of the factors that is specifically secreted by metastatic organoids – DKK3 – reduces the anti-tumor effects of natural killer cells (NKCs). Altogether, our data provides promising new targets concerning the role of SMAD4 perturbation and metastatic disease in CRC.

2022-12-11 | PXD036441 | Pride

Metastatic site influences driver gene function in pancreatic cancer [InVitro RNA-Seq]

Project description:Driver gene mutations can increase the metastatic potential of the primary tumor, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of SMAD4 – a transcriptional effector of TGFβ signaling – which is a hallmark of multiple gastrointestinal malignancies. SMAD4 inactivation mediates TGFβ’s remarkable anti- to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis. To determine whether metastatic tumors remain dependent on SMAD4 inactivation, we developed a mouse model of pancreatic ductal adenocarcinoma (PDAC) that enables Smad4 depletion in the pre-malignant pancreas and subsequent Smad4 reactivation in established metastases. As expected, Smad4 inactivation facilitated the formation of primary tumors that eventually colonized the liver and lungs. By contrast, Smad4 reactivation in metastatic disease had opposite effects depending on the tumor’s organ of residence: suppression of liver metastases and promotion of lung metastases. Integrative multiomic analysis revealed organ-specific differences in the tumor cells’ epigenomic state, whereby the liver and lungs harbored chromatin programs respectively dominated by the KLF and RUNX developmental transcription factors, with Klf4 depletion being sufficient to reverse Smad4’s tumor-suppressive activity in liver metastases. Our results show how epigenetic states favored by the organ of residence can influence the function of driver genes in metastatic tumors. This organ-specific gene–chromatin interplay invites consideration of anatomical site in the interpretation of tumor genetics, with implications for the therapeutic targeting of metastatic disease.

2025-06-12 | GSE299633 | GEO

Metastatic site influences driver gene function in pancreatic cancer [[InVitro ATAC-Seq]]

2025-06-12 | GSE299635 | GEO