Defining the role of the microbiome in cellular plasticity of colorectal cancer progression and therapy resistance

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

Enhanced cellular plasticity that facilitates the transitioning between cell states is a hallmark of cancer and has been linked to cancer progression and therapy resistance. However, in colorectal cancer (CRC) the functional role of high plasticity cell states and the cell-intrinsic and -extrinsic factors that drive the changes between cell states are mainly elusive. We propose that complex transcriptional, epigenetic, and microbial changes are interconnected and foster enhanced phenotypic plasticity of metastatic and therapy resistant CRC. Highly plastic cell states, such as foetal-like states marked by TROP2, support the progression and treatment failure of CRC. However, the exact changes, sequence and mechanisms leading to the induction of these states in treatment resistance and progression in a longitudinal manner are still largely unknown. We, therefore, aim to dissect underlying mechanisms that interconnect the microbiome and its metabolome with cell states, epigenetic dynamics and cellular plasticity to define actionable targets. To study longitudinal changes, we will utilise a novel CRISPR-Cas9 somatic genome editing mouse model from the Jackstadt group. This tool enables dissection of genotype-phenotype associations and faithfully recapitulates human CRC. Multi-omics analysis on single cell level (epigenome and transcriptome) combined with temporal and functional analysis of the microbiome along the progression of CRC will shed light on the role of the microbiome. Using our expertise in computational modelling of gene regulatory networks and cellular plasticity we will address and define the critical steps in developing temporal plasticity shaped by the microbiota composition in CRC. Together, we aim to model and functionally validate the impact of the microbiome on the cell state continuum in CRC progression and treatment resistance.

• 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: Judith Zaugg, Ph.D.