Programming gene expression in multicellular organisms for physiology modulation through engineered bacteria.
Ontology highlight
ABSTRACT:
SUBMITTER: Gao B
PROVIDER: S-EPMC8113242 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ABSTRACT Bacteria can be genetically engineered to act as therapeutic delivery vehicles in the treatment of tumors, killing cancer cells or activating the immune system. This is known as bacteria-mediated cancer therapy (BMCT). Tumor invasion, colonization and tumor regression are major biological events, which are directly associated with antitumor effects and are uncontrollable due to the influence of tumor microenvironments during the BMCT process. Here, we developed a genetic circuit for dynamically programming bacterial lifestyles (planktonic, biofilm or lysis), to precisely manipulate the process of bacterial adhesion, colonization and drug release in the BMCT process, via hierarchical modulation of the lighting power density of near-infrared (NIR) light. The deep tissue penetration of NIR offers us a modality for spatio-temporal and non-invasive control of bacterial genetic circuits in vivo. By combining computational modeling with a high-throughput characterization device, we optimized the genetic circuits in engineered bacteria to program the process of bacterial lifestyle transitions by altering the illumination scheme of NIR. Our results showed that programming intratumoral bacterial lifestyle transitions allows precise control of multiple key steps throughout the BMCT process and therapeutic efficacy can be greatly improved by controlling the localization and dosage of therapeutic agents via optimizing the illumination scheme. Programming intratumoral bacterial life style transitions allow precise control of multiple key steps throughout the bacteria-mediated cancer therapy process and therapeutic efficacy can be greatly improved by controlling the localization and dosage of therapeutic agents via optimizing the illumination scheme.
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Project description:Noisy gene expression is of fundamental importance to single cells, and is therefore widely studied in single-celled organisms. Extending these studies to multicellular organisms is challenging since their cells are generally not isolated, but individuals in a tissue. Cell-cell coupling via signalling, active transport or pure diffusion, ensures that tissue-bound cells are neither fully independent of each other, nor an entirely homogeneous population. In this article, we show that increasing the strength of coupling between cells can either increase or decrease the single-cell variability (and, therefore, the heterogeneity of the tissue), depending on the statistical properties of the underlying genetic network. We confirm these predictions using spatial stochastic simulations of simple genetic networks, and experimental data from animal and plant tissues. The results suggest that cell-cell coupling may be one of several noise-control strategies employed by multicellular organisms, and highlight the need for a deeper understanding of multicellular behaviour.
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Project description:PurposeIn the programming of tumor-targeting bacteria, various therapeutic or reporter genes are expressed by different gene-triggering strategies. Previously, we engineered pJL87 plasmid with an inducible bacterial drug delivery system that simultaneously co-expressed two genes for therapy and imaging by a bidirectional tet promoter system only in response to the administration of exogenous doxycycline (Doxy). In this multi-cassette expression approach, tetA promoter (PtetA) was 100-fold higher in expression strength than tetR promoter (PtetR). In the present study, we developed pJH18 plasmid with novel Doxy-inducible gene expression system based on a tet promoter.ProceduresIn this system, Tet repressor (TetR) expressed by a weak constitutive promoter binds to tetO operator, resulting in the tight repression of gene expressions by PtetA and PtetR, and Doxy releases TetR from tetO to de-repress PtetA and PtetR.ResultsIn Salmonella transformed with pJH18, the expression balance of bidirectional tet promoters in pJH18 was remarkably improved (PtetA:PtetR = 4~6:1) compared with that of pJL87 (PtetA:PtetR = 100:1) in the presence of Doxy. Also, the expression level by novel tet system was much higher in Salmonella transformed with pJH18 than in those with pJL87 (80-fold in rluc8 and 5-fold in clyA). Interestingly, pJH18 of the transformed Salmonella was much more stably maintained than pJL87 in antibiotic-free tumor-bearing mice (about 41-fold), because only pJH18 carries bom sequence with an essential role in preventing the plasmid-free population of programmed Salmonella from undergoing cell division.ConclusionsOverall, doxycycline-induced co-expression of two proteins at similar expression levels, we exploited bioluminescence reporter proteins with preclinical but no clinical utility. Future validation with clinically compatible reporter systems, for example, suitable for radionuclide imaging, is necessary to develop this system further towards potential clinical application.
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2021-07-13 | PXD027167 | Pride