Combining synthetic biology and organ-on-a-chip technology to develop molecular and microbial co-treatment strategies for increased druggability and accessibility of key targets in CRC

• Applicant: Dr. Antonia Schubert
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537604907

Our increasing understanding of the multifaceted role of microbiota, along with growing capabilities in genetic engineering has led to the rise of new treatment forms. This includes live therapeutics, which are ushering in a new era of precision medicine. In this project, we will integrate tailored therapeutic bacterial vectors and means to monitor tumour-microbiota interactions in real-time. To achieve this aim, we will combine genetic engineering and organ-on-a-chip technology to study signalling processes in the tumour–microbe–drug interplay via optimising an existing custom-made prototype of an organ-on-a-chip model. As a use case for applying these innovative tools in mechanistic studies, we will set a focus on the analysis of Wnt signalling, a key pathway in tumour initiation, progression, and therapeutic resistance. For this we will employ CRISPR/Cas9-mediated genome engineering, including fluorescent labelling of target proteins, to characterise the tumour–drug–microbiota interaction and the effects on Wnt signalling components via live-cell monitoring of signalling activation using advanced image-based readouts. Building on the gained mechanistic insights, we aim to design and assess therapeutic bacterial vectors for Wnt-targeted colorectal (CRC) therapy. Finally, as a proof-of-concept, we plan to evaluate the impact of these therapeutic bacteria and new treatment combinations on CRC and its microbiota in ex vivo models and in an in vivo CRC mouse model.

• DFG Programme: Research Units
• Subproject of: FOR 5806: Functional Genomics and Microbiomics in Precision Medicine of Colorectal Cancer (GenoMiCC)
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partner: Professorin Dr. Simone Schürle