Cellular heterogeneity mediates inherent sensitivity-specificity tradeoff in cancer targeting by Synthetic circuits

Mathieu Morel, Roman Shtrahman, Varda Rotter, Lior Nissim, Roy H. Bar-Ziv*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)8133-8138
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number29
DOIs
StatePublished - 19 Jul 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank Prof. Takeharu Nagai (Osaka University) who kindly provided the Sirius gene. M.M. acknowledges the Dean of Faculty Fellowship (Weizmann Institute).

Keywords

  • Cancer gene therapy
  • Cell-state targeting
  • Cellular heterogeneity
  • Mammalian synthetic biology
  • Synthetic gene circuits

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