Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability
The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metasta...
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| Format: | Article |
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American Association for the Advancement of Science (AAAS)
2018
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| Online Access: | http://hdl.handle.net/1721.1/116976 |
| _version_ | 1811002870220193792 |
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| author | Pattabiraman, D. R. Bierie, B. Kober, K. I. Thiru, P. Krall, J. A. Zill, C. Reinhardt, F. Tam, W. L. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Pattabiraman, D. R. Bierie, B. Kober, K. I. Thiru, P. Krall, J. A. Zill, C. Reinhardt, F. Tam, W. L. |
| author_sort | Pattabiraman, D. R. |
| collection | MIT |
| description | The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state. |
| first_indexed | 2024-09-23T15:55:24Z |
| format | Article |
| id | mit-1721.1/116976 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:55:24Z |
| publishDate | 2018 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1169762022-09-29T17:05:42Z Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability Pattabiraman, D. R. Bierie, B. Kober, K. I. Thiru, P. Krall, J. A. Zill, C. Reinhardt, F. Tam, W. L. Massachusetts Institute of Technology. Department of Biology Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology) The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state. 2018-07-13T15:20:13Z 2018-07-13T15:20:13Z 2016-01 2015-09 2018-07-12T16:36:33Z Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/116976 Pattabiraman, D. R. et al. “Activation of PKA Leads to Mesenchymal-to-Epithelial Transition and Loss of Tumor-Initiating Ability.” Science 351, 6277 (March 2016): aad3680 © 2016 American Association for the Advancement of Science http://dx.doi.org/10.1126/SCIENCE.AAD3680 Science Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Pattabiraman, D. R. Bierie, B. Kober, K. I. Thiru, P. Krall, J. A. Zill, C. Reinhardt, F. Tam, W. L. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability |
| title | Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability |
| title_full | Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability |
| title_fullStr | Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability |
| title_full_unstemmed | Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability |
| title_short | Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability |
| title_sort | activation of pka leads to mesenchymal to epithelial transition and loss of tumor initiating ability |
| url | http://hdl.handle.net/1721.1/116976 |
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