title: A tunable dual-promoter integrator for targeting of cancer cells.
abstract: Precise discrimination between similar cellular states is essential for autonomous decision-making scenarios, such as in vivo targeting of diseased cells. Discrimination could be achieved by delivering an effector gene expressed under a highly active context-specific promoter. Yet, a single-promoter approach has linear response and offers limited control of specificity and efficacy. Here, we constructed a dual-promoter integrator, which expresses an effector gene only when the combined activity of two internal input promoters is high. A tunable response provides flexibility in choosing promoter inputs and effector gene output. Experiments using one premalignant and four cancer cell lines, over a wide range of promoter activities, revealed a digital-like response of input amplification following a sharp activation threshold. The response function is cell dependent with its overall magnitude increasing with degree of malignancy. The tunable digital-like response provides robustness, acts to remove input noise minimizing false-positive identification of cell states, and improves targeting precision and efficacy.
authors.affiliation: Department of Materials and Interfaces, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Nissim
authors.forename: Roy H
authors.initials: RH
authors.lastname: Bar-Ziv
mesh_terms: D045744:Cell Line, Tumor; D015870:Gene Expression; D020869:Gene Expression Profiling; D018390:Gene Targeting / Q000379:methods*; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D049409:Luciferases, Firefly; D009369:Neoplasms / Q000235:genetics*; D010957:Plasmids; D011401:Promoter Regions, Genetic
chemical_list: D049409:Luciferases, Firefly