Cellular heterogeneity mediates inherent sensitivity-specificity tradeoff in cancer targeting by synthetic circuits
Abstract
The recent advance in the use of viral vectors for gene delivery, combined with the design of synthetic gene circuits to diagnose and target cells, brings opportunities for effective treatment of cancer. So far, gene circuits have been considered logical devices capable of discriminating normal from malignant cells as discrete states, ignoring cellular heterogeneity in cancer expression markers. We addressed the inherent limitations heterogeneity imposes on the precision of targeting circuits. Using molecular parameters to control circuit gain amplification and threshold, we show an inherent tradeoff emerges between specificity and sensitivity. In light of this tradeoff, the molecular optimization of targeting circuits will be an important step for effective implementation of personalized gene therapy.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- July 2016
- DOI:
- 10.1073/pnas.1604391113
- Bibcode:
- 2016PNAS..113.8133M
- Keywords:
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- synthetic gene circuits;
- cellular heterogeneity;
- cancer gene therapy;
- cell-state targeting;
- mammalian synthetic biology