Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor.
Epithelial-mesenchymal transition (EMT) plays an essential role in embryonic development, wound healing, and tumor progression. Partial EMT states have been linked to metastatic dissemination and drug resistance. Several interconnected feedback loops at the RNA and protein levels control the transit...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-05-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1013076 |
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| _version_ | 1850162847386959872 |
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| author | Sebastian Höpfl Merih Özverin Helena Nowack Raluca Tamas Andrew G Clark Nicole Radde Monilola A Olayioye |
| author_facet | Sebastian Höpfl Merih Özverin Helena Nowack Raluca Tamas Andrew G Clark Nicole Radde Monilola A Olayioye |
| author_sort | Sebastian Höpfl |
| collection | DOAJ |
| description | Epithelial-mesenchymal transition (EMT) plays an essential role in embryonic development, wound healing, and tumor progression. Partial EMT states have been linked to metastatic dissemination and drug resistance. Several interconnected feedback loops at the RNA and protein levels control the transition between different cellular states. Using a combination of mathematical modeling and experimental analyses in the TGFβ-responsive breast epithelial MCF10A cell model, we identify a central role for the tumor suppressor protein Deleted in Liver Cancer 1 (DLC1) during EMT. By extending a previous model of EMT comprising key transcription factors and microRNAs, our work shows that DLC1 acts as a positive regulator of TGFβ-driven EMT, mainly by promoting SNAIL1 expression. Our model predictions indicate that DLC1 loss impairs EMT progression. Experimental analyses confirm this prediction and reveal the acquisition of a partial EMT phenotype in DLC1-depleted cells. Furthermore, our model results indicate a possible EMT reversion to partial or epithelial states upon DLC1 loss in MCF10A cells induced toward mesenchymal phenotypes. The increased EMT plasticity of cells lacking DLC1 may explain its importance as a tumor suppressor. |
| format | Article |
| id | doaj-art-5fa776c9bcc844ce8bda139eb815a09c |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-5fa776c9bcc844ce8bda139eb815a09c2025-08-20T02:22:26ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582025-05-01215e101307610.1371/journal.pcbi.1013076Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor.Sebastian HöpflMerih ÖzverinHelena NowackRaluca TamasAndrew G ClarkNicole RaddeMonilola A OlayioyeEpithelial-mesenchymal transition (EMT) plays an essential role in embryonic development, wound healing, and tumor progression. Partial EMT states have been linked to metastatic dissemination and drug resistance. Several interconnected feedback loops at the RNA and protein levels control the transition between different cellular states. Using a combination of mathematical modeling and experimental analyses in the TGFβ-responsive breast epithelial MCF10A cell model, we identify a central role for the tumor suppressor protein Deleted in Liver Cancer 1 (DLC1) during EMT. By extending a previous model of EMT comprising key transcription factors and microRNAs, our work shows that DLC1 acts as a positive regulator of TGFβ-driven EMT, mainly by promoting SNAIL1 expression. Our model predictions indicate that DLC1 loss impairs EMT progression. Experimental analyses confirm this prediction and reveal the acquisition of a partial EMT phenotype in DLC1-depleted cells. Furthermore, our model results indicate a possible EMT reversion to partial or epithelial states upon DLC1 loss in MCF10A cells induced toward mesenchymal phenotypes. The increased EMT plasticity of cells lacking DLC1 may explain its importance as a tumor suppressor.https://doi.org/10.1371/journal.pcbi.1013076 |
| spellingShingle | Sebastian Höpfl Merih Özverin Helena Nowack Raluca Tamas Andrew G Clark Nicole Radde Monilola A Olayioye Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor. PLoS Computational Biology |
| title | Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor. |
| title_full | Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor. |
| title_fullStr | Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor. |
| title_full_unstemmed | Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor. |
| title_short | Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor. |
| title_sort | integrated mathematical and experimental modeling uncovers enhanced emt plasticity upon loss of the dlc1 tumor suppressor |
| url | https://doi.org/10.1371/journal.pcbi.1013076 |
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