Nidogen 1-Enriched Extracellular Vesicles Promote Liver Metastasis by Inducing EMT and Activating Stellate Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Guiyu Wang
PROVIDER: PXD067442 | iProX | Mon Aug 18 00:00:00 BST 2025
REPOSITORIES: iProX
Similar Datasets
Project description:Nidogen 1-Enriched Extracellular Vesicles Promote Liver Metastasis by Inducing EMT and Activating Stellate Cells
2025-10-22 | PXD069759 |
Project description:The liver is frequently affected by metastasis in colorectal cancer patients; however, the precise interaction between the liver microenvironment and metastatic colorectal cancer cells remains elusive. Our study reveals that NID1, present in extracellular vesicles (EVs) derived from metastatic colorectal cancer, plays a pivotal role in promoting colorectal cancer liver metastasis (CRLM). EV-NID1 facilitates epithelial-mesenchymal transition (EMT) in colorectal cancer cells by modulating EMT-associated genes. Moreover, EV-NID1 activates hepatic stellate cells (HSCs), which in turn stimulate neutrophil infiltration and induce the formation of neutrophil extracellular traps (NETs) within the hepatic metastatic microenvironment via interleukin 11 (IL-11) secretion. This process ultimately reshapes the tumor microenvironment (TME) and fosters the establishment of a metastatic niche conducive to CRLM. Notably, targeted inhibition of IL-11 signaling using anti-IL-11 monoclonal antibodies effectively suppresses EV-NID1-induced liver metastasis in a murine model. In summary, our findings elucidate the mechanism underlying EV-NID1-mediated regulation of CRLM, presenting a promising therapeutic target for intervention in this disease.
2025-08-01 | GSE263027 | GEO
Project description:We aimed to study the interaction of PNETs and pancreatic stellate cells (PSCs) in PNET progression through exploring specific gene expression of PNETs cultured with conditional media of PSCs.
2024-02-22 | GSE167321 | GEO
Project description:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.
2019-12-17 | GSE113279 | GEO
Project description:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.
2019-12-17 | GSE113288 | GEO
Project description:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.
2019-12-17 | GSE113283 | GEO
Project description:Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the upregulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.
2020-05-20 | GSE150874 | GEO
Project description:Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the upregulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.
2020-05-20 | GSE150873 | GEO
Project description:Depletion of Zeb1 in a KPC-model for pancreatic cancer affected strongly the formation of precursor lesions, tumour grading, invasion and notably metastasis during PDAC progression. In this context, EMT is important for metastasis, but there is variability and specificity (and not redundancy) in the role and function of different EMT-inducing transcription factors.
2017-03-16 | GSE87472 | GEO
Project description:Recent fate mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that it failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumor cells in a paracrine manner in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI-926, a Smoothened inhibitor, blocks this effect, and inhibits growth in PDX models. In human breast tumors, the EMT-TFs strongly correlate with activated Hedgehog/GLI signaling, but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis in part via non-cell autonomous effects that activate the Hh pathway. While all Hh inhibitors may act against tumors with canonical Hh/GLI signaling, only GLI inhibitors would act against EMT-induced GLI activation. In recent years, immunohistochemical analyses and multiplex high-throughput single cell sequencing of human tumor cells have shown that tumors are composed of diverse cell subpopulations containing different driver mutations, gene and protein expression profiles, growth rates, and responses to chemotherapeutics. Such heterogeneity is exacerbated by cellular plasticity, where some cells may undergo oncogenic epithelial-to-mesenchymal transition (EMT), resulting in loss of cell-cell adhesion and polarity, reduced epithelial and elevated mesenchymal protein expression, increased migration and invasion, and enhanced dissemination from the primary tumor. Because metastases in patients appear epithelial, the reverse process, mesenchymal-to-epithelial transition (MET), may occur to allow tumor cell colonization in secondary metastatic sites, establishing cellular plasticity as an important aspect of tumor progression. However, the role of EMT in carcinoma metastasis is controversial. Recent lineage tracing studies argue against the requirement of EMT for metastasis, as reporter-tagged cells that underwent a previous EMT were not found at the secondary site. However, these studies did not address the potential cooperation between EMT and non-EMT cells during the metastatic process, as EMT cancer cells may enable non-EMT cells to gain access to the secondary site, leading to macrometastatic growth. Thus, metastasis can be influenced by intratumoral heterogeneity: where a small proportion of primary tumor cells that have undergone an EMT may influence neighboring, non-EMT tumor cells. Twist1, Snail1, and Six1 are EMT-inducing transcription factors (EMT-TFs) that have all been associated with breast cancer metastasis. All three EMT-TFs regulate critical developmental processes such as cell survival, migration and invasion; in part by influencing EMT. In addition, they are downregulated post-embryogenesis, but re-expressed in various cancers where they cell autonomously induce EMT, resulting in increased percentages of tumor initiating cells (TICs) and enhanced metastasis. In carcinomas, Twist1 and Snail1 transcriptionally repress E-Cadherin (E- Cad) and upregulate mesenchymal genes. Similarly, Six1 overexpression induces EMT by regulating E-Cad localization and altering other EMT markers. During development and cancer, EMT-TFs act in concert with several signaling networks including TGFβ, Wnt, and Hedghog (Hh). The Hedgehog (Hh) signaling pathway is a prominent regulator of embryonic development, where Hh ligands function as morphogens to control numerous developmental processes. Interestingly, in Drosophila eye development, hh is a direct target of sine oculis (the homolog of Six1) and Six1 regulates Hh/GLI signaling during lung development and in fibroblasts. Additionally, Twist1 and Hh/GLI signaling are intimately linked during development, and recently Twist1 and Snail1 were associated with the Hh pathway in TICs. In mammals, canonical activation of Hh/GLI signaling involves binding of one the Hh ligands such as(either, Desert (DHH), Indian (IHH), or Sonic Hedgehog (SHH) to Patched-1 (PTCH1) or Patched-2 (PTCH2) receptors, relieving the inhibitory activity of PTCH on Smoothened (SMO). When inhibition is relieved, levels of the transcriptional activator forms of one or more GLI transcription factors (GLI1, 2, or 3) increase in the nucleus, resulting in activation of Hh target genes 12. Non-canonical activation of the GLI TFs can occur in a Hh- or SMO-independent manner via secreted factors like TGF-β19. Importantly, autocrine and paracrine Hh-mediated crosstalk between tumor cells and the tumor microenvironment 20 results in increased proliferation, stem cell self-renewal and metastasis in various cancers 21. In basal cell carcinoma (BCC) and medulloblastoma, activated Hh signaling is often due to mutations in pathway components such as PTCH and SMO, while in other tumor types including breast, mutations are not observed at high frequency. Instead there is evidence for Hh ligand-dependent pathway hyperactivity. Because numerous studies link Hh signaling to progression in multiple tumor types, derivatives of cyclopamine (e.g. GDC-0449 and IPI926), a naturally occurring plant-derived steroidal alkaloid which targets SMO, are in clinical trials for select patients with BCC and medulloblastoma with promising efficacy. However, these inhibitors have not shown promise in breast cancer despite evidence for activation of this pathway. Herein, we demonstrate that EMT-TFs Twist1, Snail1 and Six1 influence neighboring carcinoma cells in a non-cell autonomous manner, by increasing EMT features and aggressive properties of cells not expressing these TFs. Six1 is a key mediator of the non-cell autonomous effects downstream of Twist1 and Snail1, and can induce metastasis of non-Six1, non-EMT cells. All three EMT-TFs function non-cell autonomously by activation of GLI-mediated transcription in non-EMT cells, but employ different mechanisms of pathway activation, some of which are Hh ligand and SMO-independent. We find that pharmacological inhibition of GLI, but not SMO, in the non-EMT cells efficiently inhibits the non-cell autonomous phenotypes imparted by all three EMT-TFs. Importantly, we demonstrate that in selected patient derived breast cancer xenograft (PDX) models endogenously expressing high levels of these EMT-TFs (but not Hh ligands), GANT61 (a GLI1/2 inhibitor) inhibits tumor growth whereas IPI926 (a SMO inhibitor) did not. Our data suggest that upstream SMO inhibitors may not prove efficacious in tumors where a proportion of cells activate GLI-TF via EMT-TFs, and instead argue that inhibitors directly targeting GLI may be more effective.
2017-04-13 | GSE97726 | GEO