Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer Cells
Non-genetic heterogeneity is emerging as a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops invo...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Entropy |
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| Online Access: | https://www.mdpi.com/1099-4300/23/3/288 |
| _version_ | 1827588176203481088 |
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| author | Divyoj Singh Federico Bocci Prakash Kulkarni Mohit Kumar Jolly |
| author_facet | Divyoj Singh Federico Bocci Prakash Kulkarni Mohit Kumar Jolly |
| author_sort | Divyoj Singh |
| collection | DOAJ |
| description | Non-genetic heterogeneity is emerging as a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops involving (a) oscillations in androgen receptor (AR) signaling mediated through an intrinsically disordered protein PAGE4, (b) multistability in epithelial–mesenchymal transition (EMT), and (c) Notch–Delta–Jagged signaling mediated cell-cell communication, each of which can generate non-genetic heterogeneity through multistability and/or oscillations. Our results show how different coupling strengths between AR and EMT signaling can lead to monostability, bistability, or oscillations in the levels of AR, as well as propagation of oscillations to EMT dynamics. These results reveal the emergent dynamics of coupled oscillatory and multi-stable systems and unravel mechanisms by which non-genetic heterogeneity in AR levels can be generated, which can act as a barrier to most existing therapies for prostate cancer patients. |
| first_indexed | 2024-03-09T00:29:41Z |
| format | Article |
| id | doaj.art-a9f0f618920b4e1daa671771610305a0 |
| institution | Directory Open Access Journal |
| issn | 1099-4300 |
| language | English |
| last_indexed | 2024-03-09T00:29:41Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Entropy |
| spelling | doaj.art-a9f0f618920b4e1daa671771610305a02023-12-11T18:38:45ZengMDPI AGEntropy1099-43002021-02-0123328810.3390/e23030288Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer CellsDivyoj Singh0Federico Bocci1Prakash Kulkarni2Mohit Kumar Jolly3Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, IndiaCenter for Theoretical Biological Physics, Rice University, Houston, TX 77005, USADepartment of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USACentre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, IndiaNon-genetic heterogeneity is emerging as a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops involving (a) oscillations in androgen receptor (AR) signaling mediated through an intrinsically disordered protein PAGE4, (b) multistability in epithelial–mesenchymal transition (EMT), and (c) Notch–Delta–Jagged signaling mediated cell-cell communication, each of which can generate non-genetic heterogeneity through multistability and/or oscillations. Our results show how different coupling strengths between AR and EMT signaling can lead to monostability, bistability, or oscillations in the levels of AR, as well as propagation of oscillations to EMT dynamics. These results reveal the emergent dynamics of coupled oscillatory and multi-stable systems and unravel mechanisms by which non-genetic heterogeneity in AR levels can be generated, which can act as a barrier to most existing therapies for prostate cancer patients.https://www.mdpi.com/1099-4300/23/3/288non-genetic heterogeneitymultistabilityoscillationsprostate cancerfeedback loopsPAGE4 |
| spellingShingle | Divyoj Singh Federico Bocci Prakash Kulkarni Mohit Kumar Jolly Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer Cells Entropy non-genetic heterogeneity multistability oscillations prostate cancer feedback loops PAGE4 |
| title | Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer Cells |
| title_full | Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer Cells |
| title_fullStr | Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer Cells |
| title_full_unstemmed | Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer Cells |
| title_short | Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-Genetic Heterogeneity in Prostate Cancer Cells |
| title_sort | coupled feedback loops involving page4 emt and notch signaling can give rise to non genetic heterogeneity in prostate cancer cells |
| topic | non-genetic heterogeneity multistability oscillations prostate cancer feedback loops PAGE4 |
| url | https://www.mdpi.com/1099-4300/23/3/288 |
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