Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits
Synthetic gene circuits are emerging as a versatile means to target cancer with enhanced specificity by combinatorial integration of multiple expression markers. Such circuits must also be tuned to be highly sensitive because escape of even a few cells might be detrimental. However, the error rates...
| Main Authors: | , , , , |
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| Format: | Article |
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National Academy of Sciences (U.S.)
2018
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| Online Access: | http://hdl.handle.net/1721.1/115130 https://orcid.org/0000-0001-6495-4741 |
| _version_ | 1826201529566101504 |
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| author | Morel, Mathieu Shtrahman, Roman Rotter, Varda Nissim, Lior Bar-Ziv, Roy H. |
| author2 | Massachusetts Institute of Technology. Research Laboratory of Electronics |
| author_facet | Massachusetts Institute of Technology. Research Laboratory of Electronics Morel, Mathieu Shtrahman, Roman Rotter, Varda Nissim, Lior Bar-Ziv, Roy H. |
| author_sort | Morel, Mathieu |
| collection | MIT |
| description | Synthetic gene circuits are emerging as a versatile means to target cancer with enhanced specificity by combinatorial integration of multiple expression markers. Such circuits must also be tuned to be highly sensitive because escape of even a few cells might be detrimental. However, the error rates of decision-making circuits in light of cellular variability in gene expression have so far remained unexplored. Here, we measure the single-cell response function of a tunable logic AND gate acting on two promoters in heterogeneous cell populations. Our analysis reveals an inherent tradeoff between specificity and sensitivity that is controlled by the AND gate amplification gain and activation threshold. We implement a tumor-mimicking cellculture model of cancer cells emerging in a background of normal ones, and show that molecular parameters of the synthetic circuits control specificity and sensitivity in a killing assay. This suggests that, beyond the inherent tradeoff, synthetic circuits operating in a heterogeneous environment could be optimized to efficiently target malignant state with minimal loss of specificity. Keywords: synthetic gene circuits; cellular heterogeneity; cancer gene therapy; cell-state targeting; mammalian synthetic biology |
| first_indexed | 2024-09-23T11:53:11Z |
| format | Article |
| id | mit-1721.1/115130 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:53:11Z |
| publishDate | 2018 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1151302022-09-27T22:36:44Z Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits Morel, Mathieu Shtrahman, Roman Rotter, Varda Nissim, Lior Bar-Ziv, Roy H. Massachusetts Institute of Technology. Research Laboratory of Electronics Massachusetts Institute of Technology. Synthetic Biology Center Nissim, Lior Synthetic gene circuits are emerging as a versatile means to target cancer with enhanced specificity by combinatorial integration of multiple expression markers. Such circuits must also be tuned to be highly sensitive because escape of even a few cells might be detrimental. However, the error rates of decision-making circuits in light of cellular variability in gene expression have so far remained unexplored. Here, we measure the single-cell response function of a tunable logic AND gate acting on two promoters in heterogeneous cell populations. Our analysis reveals an inherent tradeoff between specificity and sensitivity that is controlled by the AND gate amplification gain and activation threshold. We implement a tumor-mimicking cellculture model of cancer cells emerging in a background of normal ones, and show that molecular parameters of the synthetic circuits control specificity and sensitivity in a killing assay. This suggests that, beyond the inherent tradeoff, synthetic circuits operating in a heterogeneous environment could be optimized to efficiently target malignant state with minimal loss of specificity. Keywords: synthetic gene circuits; cellular heterogeneity; cancer gene therapy; cell-state targeting; mammalian synthetic biology 2018-05-01T17:12:17Z 2018-05-01T17:12:17Z 2016-07 2016-03 2018-04-13T18:37:16Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/115130 Morel, Mathieu et al. “Cellular Heterogeneity Mediates Inherent Sensitivity–specificity Tradeoff in Cancer Targeting by Synthetic Circuits.” Proceedings of the National Academy of Sciences 113, 29 (July 2016): 8133–8138 © 2016 National Academy of Sciences https://orcid.org/0000-0001-6495-4741 http://dx.doi.org/10.1073/pnas.1604391113 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Sciences |
| spellingShingle | Morel, Mathieu Shtrahman, Roman Rotter, Varda Nissim, Lior Bar-Ziv, Roy H. Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits |
| title | Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits |
| title_full | Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits |
| title_fullStr | Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits |
| title_full_unstemmed | Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits |
| title_short | Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits |
| title_sort | cellular heterogeneity mediates inherent sensitivity specificity tradeoff in cancer targeting by synthetic circuits |
| url | http://hdl.handle.net/1721.1/115130 https://orcid.org/0000-0001-6495-4741 |
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