Calcium signaling induces a partial EMT in carcinoma cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157892 | GEO | 2020/09/15
REPOSITORIES: GEO
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Project description:Calcium signaling induces a partial EMT in carcinoma cells
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Project description:Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.
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Project description:Epithelial-mesenchymal transition (EMT) is a multistep process of cell de-differentiation which confers carcinoma cells with a variety of malignant characteristics. Due to the transient and reversible nature of the process, cancer cells may transit between various stages of an EMT continuum, including epithelial, partial EMT or full EMT, and the actual status of cancer cells, the kinetics of cellular state transition in vivo and the consequences thereof have remained elusive. We have established tamoxifen inducible dual recombinase lineage tracing systems combined with live cell imaging and 5-cell RNA-sequencing analysis to track cancer cells undergoing a partial or a full EMT in the MMTV-PyMT mouse model of metastatic breast cancer. In primary tumours, cancer cells infrequently undergo an EMT, and most of these cells transition between epithelial and partial EMT states, but rarely undergo a full EMT. Consequently, cells that have ever undergone a partial EMT dynamically transit between various EMT states, and they contribute to lung metastasis and chemoresistance. In contrast, full EMT cells mostly retain a mesenchymal phenotype and stably reside in perivascular regions, but fail to colonize the lungs. However, full EMT cancer cells are enriched in recurrent tumors upon chemotherapy. Our findings suggest that cancer cells in various stages of the EMT continuum contribute differentially to hallmarks of breast cancer malignancy, such as cell migration, invasion, metastasis and chemoresistance.
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Project description:Retinal pigment epithelium (RPE) stress and injury often leads to epithelial to mesenchymal transition (EMT), in which RPE cells lose its cobblestone morphology and acquire more motile and spindle-shaped fibroblast phenotype. RPE dysfunction due to acquired EMT phenotype have been implicated in a number of retinal diseases such as proliferative vitreoretinopathy (PVR), diabetic retinopathy (DR), neovascular (“wet”) and atrophic (“dry”) age-related macular degeneration (AMD). We investigated distinct temporal protein expression changes and signaling events that occur during enzymatically dissociated hRPE EMT model, as well as those that occur up to forty-eight hours after EMT onset. Further, we compared analysis on altered proteome profiling with malignancy associated EMT and AMD models. Together, proteome profiles provide a comprehensive RPE EMT resources for understanding molecular signaling events, associated biological pathways, that underlie RPE-EMT onset and further identifying chemical modulators that could potentially inhibit RPE EMT.
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Project description:Carcinoma cells can acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT). Cancer cells that undergo EMT become invasive and resist a wide range of therapies including most chemotherapy drugs and radiation. Such cells are also able to efficiently seed primary and metastatic tumors, making them functionally indistinguishable from tumor-initiating or cancer stem-like cells (TICs or CSCs). Therefore, there is significant interest in finding vulnerabilities of cancer cells that have undergone EMT. A potent EMT-selective small molecule was discovered through a large-scale chemical screen. We used microarray analysis to understand the biological effects of this compound. HMLE_ctrl (human MECs, infected with a pBabe-shGFP retrovirus) and HMLE_Twist (human MECs, infected with a pBabe-Twist retrovirus) cells were treated with solvent control (DMSO), 5 µM or 10 µM of Cmp302 for 6 hours. Microarray analysis was performed to profile global gene expression.
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Project description:Epithelial-mesenchymal transition (EMT) plays a pivotal role for tumor progression. Recent studies have revealed the existence of distinct intermediate states in EMT (partial EMT); however, the mechanisms underlying partial EMT are not fully understood. Here, we demonstrate that αvβ3 integrin induces partial EMT, which is characterized by acquiring mesenchymal phenotypes while retaining epithelial markers. We found αvβ3 integrin to be associated with poor survival in patients with lung adenocarcinoma. Moreover, αvβ3 integrin-induced partial EMT promoted migration, invasion, tumorigenesis, stemness, and metastasis of lung cancer cells in a TGF-β-independent fashion. Additionally, TGF-β1 promoted EMT progression synergistically with αvβ3 integrin, while a TGF-β signaling inhibitor showed no effect on αvβ3 integrin-induced partial EMT. Meanwhile, the microRNA-200 family abolished the αvβ3 integrin-induced partial EMT by suppressing αvβ3 integrin cell surface expression. These findings indicate that αvβ3 integrin is a key inducer of partial EMT, and highlight a new mechanism for cancer progression.
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Project description:Modulation of several waves of gene expression during FGF-1 induced Epithelial-mesenchymal transition of carcinoma cells . In vitro FGF-1 induced EMT study using NBTII rat bladder carcinoma cells Keywords: time course ; EMT ; cancer cell line ; FGF-1
2008-02-20 | GSE5664 | GEO
Project description:Carcinoma cells can acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT). Cancer cells that undergo EMT become invasive and resist a wide range of therapies including most chemotherapy drugs and radiation. Such cells are also able to efficiently seed primary and metastatic tumors, making them functionally indistinguishable from tumor-initiating or cancer stem-like cells (TICs or CSCs). Therefore, there is significant interest in finding vulnerabilities of cancer cells that have undergone EMT. A potent EMT-selective small molecule was discovered through a large-scale chemical screen. We used microarray analysis to understand the biological effects of this compound.
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Project description:This model is an expansion of the Regan2022 - Mechanosensitive EMT model (MODEL2208050001); it includes a TGFβ signaling module and autocrine signaling in mesenchymal cells. The expanded 150-node (630 link) modular model undergoes EMT triggered by biomechanical and growth signaling crosstalk, or by TGFβ. As its predecessor, this model also reproduces the ability of the core EMT transcriptional network to maintain distinct epithelial, hybrid E/M and mesenchymal states, as well as EMT driven by mitogens such as EGF on stiff ECM. We also reproduce the observed lack of stepwise MET, in that our model's dynamics does not pass through the hybrid E/M state during MET. We show that in the absence of strong autocrine signals such as TGFβ (not included in this version), cells cannot maintain their mesenchymal state in the absence of mitogens, on softer matrices, or at high cell density. In contrast, potent autocrine signaling can stabilize the mesenchymal state in all but very dense monolayers on soft ECM. This expanded model also reproduces the inhibitory effects of TGFβ on proliferation and anoikis resistance in mesenchymal cells, as well as its ability to trigger apoptosis on soft ECM vs. EMT on stiff matrices. The model offers several experimentally testable predictions related to the effect of neighbors on partial vs. full EMT, the tug of war between mitosis and the maintenance of migratory hybrid E/M states, as well as cell cycle defects in dynamic, heterogeneous populations of epithelial, hybrid E/M and mesenchymal cells.
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Project description:The goal of this study is to characterize time course gene expression profiles during TGF-beta induced EMT. In particular, we aim to identify and characterize master transcription factors regulate the transition into partial-EMT state. A time series mRNA profile in A549 cells is generated from TGF-beta induced EMT samples during 0h,6h,12h,24h,36h,48h,72h and 96h by deep sequencing, in duplicate, using Illumina HiSeq 2500
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