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Epithelial-mesenchymal plasticity induced by discontinuous exposure to TGFβ1 increases tumorigenic potential of normal epithelial cells

ABSTRACT: In this manuscript, we used a non-genetically manipulated EMT/MET cell line model to demonstrate that epithelial mesenchymal plasticity occurring in normal cells generates co-existing phenotypically and functionally divergent cell subpopulations with increased tumorigenic potential in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE181008 | GEO | 2021/07/30

REPOSITORIES: GEO

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Epithelial-mesenchymal plasticity induced by discontinuous exposure to TGFβ1 increases tumorigenic potential of normal epithelial cells

Project description:Epithelial-mesenchymal plasticity induced by discontinuous exposure to TGFβ1 increases tumorigenic potential of normal epithelial cells

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Epithelial-Mesenchymal Plasticity Induced by Discontinuous Exposure to TGFβ1 Promotes Tumour Growth

Project description:Simple Summary In this manuscript, we used a non-genetically manipulated EMT/MET cell line model to demonstrate that epithelial mesenchymal plasticity occurring in normal cells generates co-existing phenotypically and functionally divergent cell subpopulations which result in fast growing tumours in vivo. Abstract Transitions between epithelial and mesenchymal cellular states (EMT/MET) contribute to cancer progression. We hypothesize that EMT followed by MET promotes cell population heterogeneity, favouring tumour growth. We developed an EMT model by on and off exposure of epithelial EpH4 cells (E-cells) to TGFβ1 that mimics phenotypic EMT (M-cells) and MET. We aimed at understanding whether phenotypic MET is accompanied by molecular and functional reversion back to epithelia by using RNA sequencing, immunofluorescence (IF), proliferation, wound healing, focus formation and mamosphere formation assays as well as cell xenografts in nude mice. Phenotypic reverted epithelial cells (RE-cells) obtained after MET induction presented epithelial morphologies and proliferation rates resembling E cells. However, the RE transcriptomic profile and IF staining of epithelial and mesenchymal markers revealed a uniquely heterogeneous mixture of cell subpopulations with a high self-renewal ability. RE cell heterogeneity was stably maintained for long periods after TGFβ1 removal both in vitro and in large tumours derived from the nude mice. Overall, we show that phenotypic reverted epithelial cells (RE cells) do not return to the molecular and functional epithelial state and present mesenchymal features related to aggressiveness and cellular heterogeneity that favour tumour growth in vivo. This work strengthens epithelial cell reprogramming and cellular heterogeneity fostered by inflammatory cues as a tumour growth-promoting factor in vivo.

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Mesenchymal-Epithelial Transition Regulates Initiation of Pluripotency Exit before Gastrulation

Project description:The pluripotent epiblast gives rise to all tissues and organs in an adult body. Its differentiation starts at gastrulation when the epiblast generates mesoderm and endoderm germ layers through a process called epithelial-mesenchymal transition (EMT). Although gastrulation EMT coincides with loss of epiblast pluripotency, pluripotent cells in development and in culture can adopt either mesenchymal or epithelial morphology. The relationship between epiblast pluripotency and epiblast morphology is not well understood. In this work, using chicken epiblast and human induced pluripotent stem cell (hiPSC) models, we show that pluripotent cells undergo an obligatory mesenchymal-epithelial transition (MET) prior to EMT-associated pluripotency loss. Epiblast MET and the subsequent EMT are two distinct processes. The former, a partial MET, is associated with reversible pluripotency exit; whereas the latter, a full EMT, is associated with complete and irreversible pluripotency loss. We provide evidence that integrin-mediated cell-matrix interaction, but not E-cadherin-mediated cell-cell interaction, is a key player in pluripotency exit regulation. We propose that epiblast partial MET is an evolutionarily conserved process among all amniotic vertebrates and its developmental function is to mediate planar symmetry-breaking within an epithelialized epiblast, taking place after epiblast MET but before gastrulation EMT.

2018-12-31 | GSE114476 | GEO

Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition.

Project description:Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis.

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The TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop increases the cisplatin resistance of non-small cell lung cancer by inducing G6PD expression.

Project description:Platinum-based chemotherapy is still widely applied for the treatment of advanced non-small cell lung cancer (NSCLC). However, acquired chemoresistance compromises the curative effect of this drug. In this study, we found that glucose-6-phosphate dehydrogenase (G6PD), a critical enzyme of the pentose phosphate pathway, contributed to cisplatin resistance in NSCLC. The experimental results showed that transforming growth factor beta 1 (TGFβ1) increased the expression of G6PD by activating the forkhead box protein M1-high mobility group AT-hook 1-G6PD (FOXM1-HMGA1-G6PD) transcriptional regulatory pathway, in which TGFβ1 inhibited the ubiquitination and degradation of FOXM1 protein. Additionally, HMGA1 induced TGFβ1 expression, and neutralized TGFβ1 in the culture medium downregulated HMGA1 levels, suggesting the existence of a TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop and its role in maintaining G6PD expression. Further investigations showed that exogenous TGFβ1 enhanced the cisplatin resistance of NSCLC cells, while disrupting the FOXM1-HMGA1-G6PD pathway, thereby sensitizing the cells to cisplatin. Consistently, the TGFβ1-FOXM1-HMGA1-G6PD axis was confirmed in NSCLC tissues, and overactivation of this axis predicted poor survival in NSCLC patients. Collectively, the results of this study demonstrate that the TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop plays a crucial role in the cisplatin resistance of NSCLC by upregulating the expression of G6PD, providing a potential therapeutic target to restore chemosensitivity in cisplatin-resistant NSCLC.

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Targeting epithelial-mesenchymal plasticity via ribosome inhibition to reduce chemoresistant metastasis of breast cancer [bulk RNA-seq]

Project description:Using an EMT lineage-tracing model, we identified tumor cells in the transitioning phases of both EMT and MET. Further analyses revealed that the ribosome biogenesis (RiBi) pathway was specifically elevated in these transitioning cells, regardless of their destined phenotypical fates.

2022-09-01 | GSE178576 | GEO

Chemotherapy induces cell plasticity; controlling plasticity increases therapeutic response.

Project description:One of the most serious issues in modern oncology is the ineffectiveness of treatments in destroying tumours, which leads to tumour recurrence and, ultimately, patient death To investigated this we analyze plasticity of chemotherapy-resistant cells

2024-04-09 | GSE229761 | GEO

A molecular portrait of epithelial-mesenchymal plasticity in prostate cancer associated with clinical outcome.

Project description:The propensity of cancer cells to transition between epithelial and mesenchymal phenotypic states is considered to be critical in metastatic processes, cancer progression, and treatment resistance. To investigate a transient epithelial-mesenchymal transition (EMT) in prostate adenocarcinoma, LNCaP cells with inducible and reversible expression of SNAI1 or SNAI2 were generated. Cells were treated with doxycycline to induce a SNAI1- or SNAI2-mediated EMT for 5 days and then subsequently removed for 3, 5, and 20 days to allow for MET. LNCaP-iGFP cells were also generated for control purposes and were subjected to the same treatment regime.

2018-09-11 | GSE80042 | GEO

Gene expression in epithelial, EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition) cells

Project description:NMuMG is an epithelial cell line that can be induced into EMT by TGF-β treatment or MET by TGF-β withdrawl. During EMT, several marker genes were downregulated/upregulated, which is consistent with its mesenchymal phenotype. Transcription factors that are regulated during EMT and its reverse process MET are candidate genes for the regulations of the EMT marker genes.

2013-07-26 | GSE48204 | GEO

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