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Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model

The tumor microenvironment (TME) is the source of important cues that govern epithelial-to-mesenchymal transition (EMT) and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal ph...

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Autores principales: Dhungel, Nilu, Youngblood, Reneau, Chu, Min, Carroll, Jennifer, Dragoi, Ana-Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022497/
https://www.ncbi.nlm.nih.gov/pubmed/36936987
http://dx.doi.org/10.3389/fmolb.2023.1096326
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author Dhungel, Nilu
Youngblood, Reneau
Chu, Min
Carroll, Jennifer
Dragoi, Ana-Maria
author_facet Dhungel, Nilu
Youngblood, Reneau
Chu, Min
Carroll, Jennifer
Dragoi, Ana-Maria
author_sort Dhungel, Nilu
collection PubMed
description The tumor microenvironment (TME) is the source of important cues that govern epithelial-to-mesenchymal transition (EMT) and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal phenotype. Rather, cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for cell population heterogeneity, which is advantageous for the ever-changing environment during tumor development and metastasis. How are these intermediate states generated and maintained is not fully understood. Here, we show that direct interaction between small cell lung carcinoma cells and lung fibroblasts induces a hybrid EMT phenotype in cancer cells in which several mesenchymal genes involved in receptor interaction with the extracellular matrix (ECM) and ECM remodeling are upregulated while epithelial genes such as E-cadherin remain unchanged or slightly increase. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, as is Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Further, we show that these changes are transient and reverse to the initial state once the interaction is disrupted. Altogether, our results provide evidence that tumor cells’ direct contact with the fibroblasts in the TME initiates a signaling cascade responsible for hybrid E/M states of cancer cells. These hybrid states are maintained during the interaction and possibly contribute to therapy resistance and immune evasion, while interference with direct contact will result in slow recovery and switch to the initial states.
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spelling pubmed-100224972023-03-18 Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model Dhungel, Nilu Youngblood, Reneau Chu, Min Carroll, Jennifer Dragoi, Ana-Maria Front Mol Biosci Molecular Biosciences The tumor microenvironment (TME) is the source of important cues that govern epithelial-to-mesenchymal transition (EMT) and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal phenotype. Rather, cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for cell population heterogeneity, which is advantageous for the ever-changing environment during tumor development and metastasis. How are these intermediate states generated and maintained is not fully understood. Here, we show that direct interaction between small cell lung carcinoma cells and lung fibroblasts induces a hybrid EMT phenotype in cancer cells in which several mesenchymal genes involved in receptor interaction with the extracellular matrix (ECM) and ECM remodeling are upregulated while epithelial genes such as E-cadherin remain unchanged or slightly increase. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, as is Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Further, we show that these changes are transient and reverse to the initial state once the interaction is disrupted. Altogether, our results provide evidence that tumor cells’ direct contact with the fibroblasts in the TME initiates a signaling cascade responsible for hybrid E/M states of cancer cells. These hybrid states are maintained during the interaction and possibly contribute to therapy resistance and immune evasion, while interference with direct contact will result in slow recovery and switch to the initial states. Frontiers Media S.A. 2023-03-03 /pmc/articles/PMC10022497/ /pubmed/36936987 http://dx.doi.org/10.3389/fmolb.2023.1096326 Text en Copyright © 2023 Dhungel, Youngblood, Chu, Carroll and Dragoi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Dhungel, Nilu
Youngblood, Reneau
Chu, Min
Carroll, Jennifer
Dragoi, Ana-Maria
Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model
title Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model
title_full Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model
title_fullStr Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model
title_full_unstemmed Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model
title_short Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model
title_sort assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (sclc) and lung fibroblasts co-culture model
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022497/
https://www.ncbi.nlm.nih.gov/pubmed/36936987
http://dx.doi.org/10.3389/fmolb.2023.1096326
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