Enhancing the tropism of bacteria via genetically programmed biosensors

Chien, Tiffany; Harimoto, Tetsuhiro; Kepecs, Benjamin; Gray, Kelsey; Coker, Courtney; Hou, Nicholas; Pu, Kelly; Azad, Tamjeed; Nolasco, Andoni; Pavlicová, Martina; Danino, Tal

doi:10.1038/s41551-021-00772-3

Cited by 82 publications

(57 citation statements)

References 88 publications

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“… 56 Since lactate is a major oncometabolite, the use of lactate biosensors has been proposed to restrict the activity or growth of therapeutic bacteria to tumoral tissues and avoid off-target effects, occurring with the majority of anticancer treatments. 54 To evaluate the performance of ALPaGA for tumor-specific control of gene expression, we aimed at sensing endogenous l -lactate produced by tumor spheroids.…”

Section: Results and Discussionmentioning

confidence: 99%

Engineered l-Lactate Responding Promoter System Operating in Glucose-Rich and Anoxic Environments

et al. 2021

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Bacteria equipped with genetically encoded lactate biosensors are promising tools for biopharmaceutical production, diagnostics, and cellular therapies. However, many applications involve glucose-rich and anoxic environments, in which current whole-cell lactate biosensors show low performance. Here we engineer an optimized, synthetic lactate biosensor system by repurposing the natural LldPRD promoter regulated by the LldR transcriptional regulator. We removed glucose catabolite and anoxic repression by designing a hybrid promoter, containing LldR operators and tuned both regulator and reporter gene expressions to optimize biosensor signal-to-noise ratio. The resulting lactate biosensor, termed ALPaGA (A Lactate Promoter Operating in Glucose and Anoxia), can operate in glucose-rich, aerobic and anoxic conditions. We show that ALPaGA works reliably in the probiotic chassis Escherichia coli Nissle 1917 and can detect endogenous l -lactate produced by 3D tumor spheroids with an improved dynamic range. In the future, the ALPaGA system could be used to monitor bioproduction processes and improve the specificity of engineered bacterial cancer therapies by restricting their activity to the lactate-rich microenvironment of solid tumors.

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Section: Results and Discussionmentioning

confidence: 99%

Engineered l-Lactate Responding Promoter System Operating in Glucose-Rich and Anoxic Environments

et al. 2021

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“…The authors highlight consequential B cell aplasia as a mechanism to avoid antibody responses against the OVs, however, the approach could be extended to the delivery of orthogonal CAR targets at the cost of repeat dosing. Nonetheless, the use of bacteria in the ProCAR system offers a partner organism that is amenable to complex engineering 51 , including the incorporation of additional circuits to restrict growth and immunogenicity in ways that facilitate safe systemic delivery and repeat dosing [52][53][54][55] . Moreover, the current study has highlighted natural inflammatory properties of probiotics that serve to enhance T cell effector function in an otherwise immunosuppressive-TME.…”

Section: Discussionmentioning

confidence: 99%

Probiotic-guided CAR-T cells for universal solid tumor targeting

Vincent

Gurbatri

Redenti

et al. 2021

Preprint

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Synthetic biology enables the engineering of interactions between living medicines to overcome the specific limitations of any singular therapy. One major challenge of tumor-antigen targeting therapies like chimeric antigen receptor (CAR)-T cells is the identification of targetable antigens that are specifically and uniformly expressed on heterogenous solid tumors. In contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be readily engineered as antigen-independent platforms for therapeutic delivery. Bridging these approaches, we develop a platform of probiotic-guided CAR-T cells (ProCARs), in which T cells are engineered to sense synthetic antigens (SA) that are produced and released by tumor-colonizing probiotic bacteria. We demonstrate increased CAR-T cell activation and tumor-cell lysis when SAs anchor to components of the extracellular matrix. Moreover, we show that ProCARs are intratumorally activated by probiotically-delivered SAs, receive further stimulation from bacterial TLR agonists, and are safe and effective in multiple xenograft models. This approach repurposes tumor-colonizing bacteria as beacons that guide the activity of engineered T cells, and in turn builds the foundation for communities of living medicines.

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“…Recently, work from the Tal Danino group engineered bacteria to carry a AND circuit of hypoxia and lactate sensors (Chien et al, 2021). The AND gate is built based on two transcriptional regulators.…”

Section: Biosensors For General Gut Signalsmentioning

confidence: 99%

“…As an example of integrating multiple cues, hypoxia-lactate sensing S. Typhimurium has increased tumor specificity (Chien et al, 2021). Recent work demonstrated that living cells that sense up to three signals precisely recognize targeted cancer (Williams et al, 2020).…”

Section: Need For Biomarkers Landscapes To Specifically Diagnose Dise...mentioning

confidence: 99%

The Future Potential of Biosensors to Investigate the Gut-Brain Axis

Wang

Childers

2022

Front. Bioeng. Biotechnol.

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The multifaceted and heterogeneous nature of depression presents challenges in pinpointing treatments. Among these contributions are the interconnections between the gut microbiome and neurological function termed the gut-brain axis. A diverse range of microbiome-produced metabolites interact with host signaling and metabolic pathways through this gut-brain axis relationship. Therefore, biosensor detection of gut metabolites offers the potential to quantify the microbiome’s contributions to depression. Herein we review synthetic biology strategies to detect signals that indicate gut-brain axis dysregulation that may contribute to depression. We also highlight future challenges in developing living diagnostics of microbiome conditions influencing depression.

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Enhancing the tropism of bacteria via genetically programmed biosensors

Cited by 82 publications

References 88 publications

Engineered l-Lactate Responding Promoter System Operating in Glucose-Rich and Anoxic Environments

Engineered l-Lactate Responding Promoter System Operating in Glucose-Rich and Anoxic Environments

Probiotic-guided CAR-T cells for universal solid tumor targeting

The Future Potential of Biosensors to Investigate the Gut-Brain Axis

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