TGF-β induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1255208 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The heterogeneity of epithelial-to-mesenchymal transition (EMT) programs is manifest in the diverse EMT-like phenotypes occurring during tumor progression. However, little is known about the mechanistic basis and functional role of specific forms of EMT in cancer. Here we address this question in lung adenocarcinoma (LUAD) cells that enter a dormancy period in response to TGF-β upon disseminating to distant sites. LUAD cells with the capacity to enter dormancy are characterized by expression of SOX2 and NKX2-1 primitive progenitor markers. In these cells, TGF-β induces growth inhibition accompanied by a full EMT response that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGF-β induces this transition by driving the expression of the actin-depolymerizing factor gelsolin, which changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors, protecting them from killing by mechanosensitive cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Inhibiting this actin depolymerization process clears tissues of dormant metastatic cells. Thus, LUAD primitive progenitors undergo an atypical EMT as part of a strategy to evade immune-mediated elimination during dormancy. Our results provide a mechanistic basis and functional role of this atypical EMT response of LUAD metastatic progenitors and further illuminate the role of TGF-β as a crucial driver of immune evasive metastatic dormancy.
2025-08-29 | GSE295578 | GEO
Project description:Cancer cells disseminated to distant sites enter a period of dormancy before generating overt metastases. The ability of these cells to elude immune surveillance determines their persistence as latent disease. We report that TGF-β promotes dormancy in lung adenocarcinoma (LUAD) mouse models by placing disseminated SOX2+ and NKX2-1+ progenitors in a quiescent state that biomechanically averts killing by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In these primitive progenitors, TGF-β induces an atypical epithelial-to-mesenchymal transition (EMT) lacking actin stress fibers. TGF-β drives expression of the actin-depolymerizing factor gelsolin that changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the stiffness of metastatic progenitors and their killing by mechanosensitive CTLs and NK cells. Thus, LUAD primitive progenitors activate a biomechanical process to evade immune-mediated elimination during prolonged dormancy periods. Inhibiting this process clears tissues of dormant metastatic cells.
2024-12-04 | GSE269762 | GEO
Project description:The heterogeneity of epithelial-to-mesenchymal transition (EMT) programs is manifest in the diverse EMT-like phenotypes occurring during tumor progression. However, little is known about the mechanistic basis and functional role of specific forms of EMT in cancer. Here we address this question in lung adenocarcinoma (LUAD) cells that enter a dormancy period in response to TGF-β upon disseminating to distant sites. LUAD cells with the capacity to enter dormancy are characterized by expression of SOX2 and NKX2-1 primitive progenitor markers. In these cells, TGF-β induces growth inhibition accompanied by a full EMT response that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGF-β induces this transition by driving the expression of the actin-depolymerizing factor gelsolin, which changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors, protecting them from killing by mechanosensitive cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Inhibiting this actin depolymerization process clears tissues of dormant metastatic cells. Thus, LUAD primitive progenitors undergo an atypical EMT as part of a strategy to evade immune-mediated elimination during dormancy. Our results provide a mechanistic basis and functional role of this atypical EMT response of LUAD metastatic progenitors and further illuminate the role of TGF-β as a crucial driver of immune evasive metastatic dormancy.
| S-EPMC11507679 | biostudies-literature
Project description:Transforming growth factor- (TGF-) signaling is a critical driver of epithelial–mesenchymal transition (EMT) and cancer progression. However, the regulatory roles of long non-coding RNAs (lncRNAs) in TGF--induced EMT and cancer progression are not well understood. Here, we identified an unannotated nuclear lncRNA LETS1 (LncRNA Enforcing TGF- Signaling 1) as a novel TGF-/SMAD target gene. Loss of LETS1 attenuates TGF--induced EMT, migration and extravasation in breast and lung cancer cells. LETS1 potentiates TGF-/SMAD signaling by stabilizing cell surface TGF- type I receptor (TRI) and thereby forms a positive feedback loop. Mechanistically, LETS1 inhibits TRI polyubiquitination by inducing the orphan nuclear receptor 4A1 (NR4A1) expression, a critical determinant of a destruction complex for inhibitory SMAD7. An unbiased interactome analysis identified the Nuclear Factor of Activated T Cells (NFAT5) as a protein partner of LETS1 to mediate activation of NR4A1 promoter. Overall, our findings characterize LETS1 as an EMT-promoting lncRNA and elucidate the mechanism by which nuclear LETS1 potentiates TGF- receptor signaling.
2023-07-31 | PXD037401 | Pride
Project description:TGF-β protects dormant metastasis from immune mechanosurveillance
| PRJNA1123643 | ENA
Project description:Our group is interested in epithelial-to-mesenchymal transition (EMT), in particular, TGF-beta induced EMT. TGF-beta signalling has been shown to be an important factor in the induction of EMT and it has been demonstrated that adding TGF-beta to epithelial cells in culture is a convenient way to study the process of EMT. In response to TGF-beta, Smad2 and 3 are activated, and form complexes with Smad4, which then regulate transcription of target genes through interactions with other DNA binding transcription factors. In the induction of EMT, the activated Smads mediate transcriptional regulation through three families of transcription factors, resulting in repression of epithelial marker gene expression and activation of mesenchymal gene expression (Xu J, et al. 2009) <br></br> Also investigated in this study is the role of H2A.Z in EMT. H2A.Z is an evolutionary conserved and a metazoan essential histone variant of the H2A class. Mice deficient in H2A.Z die during early development but the reason for this is unknown (Faast et al. 2001). Previously, our laboratory showed that the loss of H2A.Z in Xenpous laevis impaired cell movement required for the formation of the mesoderm and neural crest (Ridgway et al. 2004). Given that mesoderm formation is critically dependent upon EMT, we therefore wondered whether H2A.Z might be a chromatin regulator of EMT. We transfected MDCK cells with a lentiviral vector to express a construct encoding an shRNA targeting canine H2A.Z as we wanted to test the hypothesis that H2A.Z is involved in the maintenance of cellular identity and that its loss might trigger de-differentiation. <br></br> In order to investigate changes in histone variant H2A.Z occupancy associated with TGF-beta induced epithelial-to-mesenchymal transition (EMT) we performed H2A.Z ChIP-Seq in untreated and TGFb-treated MDCK cells. The MDCK cell line has been extensively used as a model system for EMT because they convert fully from the epithelial to the mesenchymal state in response to TGF-beta. <br></br>Please note that RNA-seq data generated in conjunction to this ChIP-seq data set were also deposited at ArrayExpress under accession number E-MTAB-5628 ( https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5628 ).
2017-10-23 | E-MTAB-5637 | biostudies-arrayexpress
Project description:TGF-β is a major tumor suppressor in gastrointestinal (GI) and squamous carcinomas, which exhibit frequent genetic inactivation of Smad4, a key TGF-β signaling component. Apoptosis is implicated as an important mediator of the tumor suppressive function of TGF-β, although this process remains poorly understood. To address this long-standing question, we dissected the tumor suppressive action of TGF-β in naïve pancreatic ductal adenocarcinoma (PDA) cells. Here we show that TGF-β/Smad4 signaling triggers an EMT in Kras-mutant pancreatic progenitor cells but turns this process into a trigger of apoptosis by converting the progenitor cell transcription factor Sox4 from an enforcer of epithelial progenitor identity into an activator of apoptosis. This occurs as a result of the EMT-linked repression of the endodermal master regulator Klf5, which cooperates with Sox4 to promote epithelial progenitor identity, and loss of which unmasks a latent apoptotic transcriptional program driven by Sox4. By losing Smad4, Kras-mutant PDA cells avoid this fate and instead use Sox4 as a TGF-β-dependent enforcer of the epithelial progenitor cell state. In this study, 16 RNA-Seq samples and 6 ChIP-Seq samples are included.
2016-02-24 | E-GEOD-72069 | biostudies-arrayexpress
Project description:Epithelial-to-mesenchymal transitions (EMT) play prominent roles during development, regeneration and tumor progression. EMTs are triggered by TGF-β, RAS and other signals that cooperatively induce the expression of master EMT transcription factors such as SNAIL. Here, we elucidate how the TGF-β and RAS pathways jointly trigger EMTs and tie them to broader developmental programs. We identify RAS response element binding protein 1 (RREB1) as a critical partner of TGF-β-activated SMAD transcription factors in driving SNAIL expression and EMT program in mammary gland epithelial cells.
2020-01-09 | GSE128958 | GEO
Project description:Vicious circle of some key proteins is critical in the process of tumor development. Nevertheless, the mechanism of how the epigenetic modifiers are involved in was seldom reported and has not been clearly illustrated. We found the expression of lysine specific demethylase 1 (LSD1), the first identified histone lysine demethylase, is positively correlated with transforming growth factor beta 1 (TGF β1) in gastric cancer tissues and can be promoted by TGF β1 activated (p-EKR)-(NF-κB)-p300 signaling pathway, which resulted in the progression of epithelial-mesenchymal transition (EMT) in human gastric cancer cells. On the other hand, abrogation of LSD1 leads to the down regulation of TGF β1 as well as the EMT. But in benign cells, this circle was blocked by TGF β1 induced inactivation of ERK, which suggested the distinct roles of TGF β1 against LSD1 in gastric cancer cells and benign cells. This vicious cycle may illustrate a novel mechanism for EMT in gastric cancer mediate by TGF β1 and LSD1 but not in benign cells and may serve as a new strategy for the prevention of EMT for gastric cancer. Nuclear extracts prepared from MGC803 cells stably expressing Lenti-CAS9-sgRNA-puro for LSD1 or empty vector were used in immunoprecipitation reactions with antibodies against H3K4me2 and H3K9me2. Sequencing libraries were prepared using the TruSeq DNA Sample Prep Kit (Illumina) and sequencing was performed on a HiSeq2000 (Illumina).
2016-07-19 | E-GEOD-84487 | biostudies-arrayexpress
Project description:TGF-β is a major tumor suppressor in gastrointestinal (GI) and squamous carcinomas, which exhibit frequent genetic inactivation of Smad4, a key TGF-β signaling component. Apoptosis is implicated as an important mediator of the tumor suppressive function of TGF-β, although this process remains poorly understood. To address this long-standing question, we dissected the tumor suppressive action of TGF-β in naïve pancreatic ductal adenocarcinoma (PDA) cells. Here we show that TGF-β/Smad4 signaling triggers an EMT in Kras-mutant pancreatic progenitor cells but turns this process into a trigger of apoptosis by converting the progenitor cell transcription factor Sox4 from an enforcer of epithelial progenitor identity into an activator of apoptosis. This occurs as a result of the EMT-linked repression of the endodermal master regulator Klf5, which cooperates with Sox4 to promote epithelial progenitor identity, and loss of which unmasks a latent apoptotic transcriptional program driven by Sox4. By losing Smad4, Kras-mutant PDA cells avoid this fate and instead use Sox4 as a TGF-β-dependent enforcer of the epithelial progenitor cell state.
2016-02-24 | GSE72069 | GEO