Disrupting cellular memory to overcome drug resistance
Abstract Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. However, we lack robust methods to fi...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41811-8 |
| _version_ | 1797630107135770624 |
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| author | Guillaume Harmange Raúl A. Reyes Hueros Dylan L. Schaff Benjamin Emert Michael Saint-Antoine Laura C. Kim Zijian Niu Shivani Nellore Mitchell E. Fane Gretchen M. Alicea Ashani T. Weeraratna M. Celeste Simon Abhyudai Singh Sydney M. Shaffer |
| author_facet | Guillaume Harmange Raúl A. Reyes Hueros Dylan L. Schaff Benjamin Emert Michael Saint-Antoine Laura C. Kim Zijian Niu Shivani Nellore Mitchell E. Fane Gretchen M. Alicea Ashani T. Weeraratna M. Celeste Simon Abhyudai Singh Sydney M. Shaffer |
| author_sort | Guillaume Harmange |
| collection | DOAJ |
| description | Abstract Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. However, we lack robust methods to find regulators of memory or track state switching. Here, we develop a lineage tracing-based technique to quantify memory and identify cells that switch states. Applied to melanoma cells without therapy, we quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy. We also identify the PI3K and TGF-β pathways as state switching modulators. We propose a pretreatment model, first applying a PI3K inhibitor to modulate gene expression states, then applying targeted therapy, which leads to less resistance than targeted therapy alone. Together, we present a method for finding modulators of gene expression memory and their associated cell fates. |
| first_indexed | 2024-03-11T11:02:16Z |
| format | Article |
| id | doaj.art-7b621b0b3de741a7a1b5b0d9ca428339 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-11T11:02:16Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-7b621b0b3de741a7a1b5b0d9ca4283392023-11-12T12:24:03ZengNature PortfolioNature Communications2041-17232023-11-0114111710.1038/s41467-023-41811-8Disrupting cellular memory to overcome drug resistanceGuillaume Harmange0Raúl A. Reyes Hueros1Dylan L. Schaff2Benjamin Emert3Michael Saint-Antoine4Laura C. Kim5Zijian Niu6Shivani Nellore7Mitchell E. Fane8Gretchen M. Alicea9Ashani T. Weeraratna10M. Celeste Simon11Abhyudai Singh12Sydney M. Shaffer13Cellular and Molecular Biology Graduate Group, Perelman School of Medicine, University of PennsylvaniaDepartment of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of PennsylvaniaDepartment of Bioengineering, School of Engineering and Applied Sciences, University of PennsylvaniaDivision of Biology and Biological Engineering, California Institute of TechnologyDepartment of Electrical and Computer Engineering, University of DelawareAbramson Family Cancer Research Institute, Perelman School of Medicine, University of PennsylvaniaDepartment of Chemistry, College of the Arts and Sciences, University of PennsylvaniaDepartment of Biology, College of the Arts and Sciences, University of PennsylvaniaCancer Signaling and Microenvironment Research Program, Fox Chase Cancer CenterDepartment of Biochemistry and Molecular Biology, Johns Hopkins School of Public HealthDepartment of Biochemistry and Molecular Biology, Johns Hopkins School of Public HealthAbramson Family Cancer Research Institute, Perelman School of Medicine, University of PennsylvaniaDepartment of Electrical and Computer Engineering, University of DelawareDepartment of Bioengineering, School of Engineering and Applied Sciences, University of PennsylvaniaAbstract Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. However, we lack robust methods to find regulators of memory or track state switching. Here, we develop a lineage tracing-based technique to quantify memory and identify cells that switch states. Applied to melanoma cells without therapy, we quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy. We also identify the PI3K and TGF-β pathways as state switching modulators. We propose a pretreatment model, first applying a PI3K inhibitor to modulate gene expression states, then applying targeted therapy, which leads to less resistance than targeted therapy alone. Together, we present a method for finding modulators of gene expression memory and their associated cell fates.https://doi.org/10.1038/s41467-023-41811-8 |
| spellingShingle | Guillaume Harmange Raúl A. Reyes Hueros Dylan L. Schaff Benjamin Emert Michael Saint-Antoine Laura C. Kim Zijian Niu Shivani Nellore Mitchell E. Fane Gretchen M. Alicea Ashani T. Weeraratna M. Celeste Simon Abhyudai Singh Sydney M. Shaffer Disrupting cellular memory to overcome drug resistance Nature Communications |
| title | Disrupting cellular memory to overcome drug resistance |
| title_full | Disrupting cellular memory to overcome drug resistance |
| title_fullStr | Disrupting cellular memory to overcome drug resistance |
| title_full_unstemmed | Disrupting cellular memory to overcome drug resistance |
| title_short | Disrupting cellular memory to overcome drug resistance |
| title_sort | disrupting cellular memory to overcome drug resistance |
| url | https://doi.org/10.1038/s41467-023-41811-8 |
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