title: Cellular heterogeneity mediates inherent sensitivity-specificity tradeoff in cancer targeting by synthetic circuits.
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 cell-culture 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.
authors.affiliation: Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel, 76100; Ecole Normale Supérieure, Paris Sciences et Lettres (PSL) Research University, Université Pierre et Marie Curie, CNRS, Département de Chimie, UMR 8640 PASTEUR, 75005 Paris, France; Université Pierre et Marie Curie Paris 06, École Normale Supérieure, CNRS, UMR 8640 PASTEUR, 75005 Paris, France;
authors.forename: Mathieu
authors.initials: M
authors.lastname: Morel
authors.affiliation: Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel, 76100;
authors.forename: Roman
authors.initials: R
authors.lastname: Shtrahman
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel, 76100;
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter
authors.affiliation: Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139 liorni@mit.edu roy.bar-ziv@weizmann.ac.il.
authors.forename: Lior
authors.initials: L
authors.lastname: Nissim
authors.affiliation: Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel, 76100; liorni@mit.edu roy.bar-ziv@weizmann.ac.il.
authors.forename: Roy H
authors.initials: RH
authors.lastname: Bar-Ziv
mesh_terms: D016923:Cell Death; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics; D005347:Fibroblasts; D053263:Gene Regulatory Networks; D045325:HCT116 Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics; D012680:Sensitivity and Specificity; D058615:Synthetic Biology
chemical_list: C530104:CCND1 protein, human; D006657:Histones; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D019938:Cyclin D1; C093962:synovial sarcoma X breakpoint proteins
keywords: cancer gene therapy; cell-state targeting; cellular heterogeneity; mammalian synthetic biology; synthetic gene circuits