Decipher Epithelial Transformation by Enteric bacteria in precursors of Colorectal Tumors

• Applicant: Dr. Jens Puschhof
• Subject Area: Gastroenterology ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567606376

The human gut harbors a diverse community of bacteria that closely interact with the intestinal epithelium. We have recently shown that specific strains of E. coli, via the genotoxin colibactin, induce mutations in the APC tumor suppressor gene in colorectal cancer (CRC). Especially in familial adenomatous polyposis (FAP) patients, such events may contribute to the accelerated induction and progression of adenomas. Understanding and targeting these interactions emerges as a promising strategy for delaying the onset of FAP, but also in the context of the increasing numbers of sporadic young onset CRC cases. In my Emmy Noether group, I aim to unravel the microbial contributions to early neoplastic transformation in FAP. We will systematically investigate the impact of DNA damaging bacterial strains on mutation accumulation and transformation in FAP adenomas. By integrating a substantial bacterial strain bank that we have derived from (pre)cancerous patient tissues with cutting-edge organoid and organ chip models, we will establish causal links between the microbiome and mutation-driven tumorigenesis, with a strong focus on translational applications for prevention. As Aim 1, we will identify which bacterial strains are responsible for inducing mutations and driving the transformation of FAP adenomas. We will systematically assess the mutagenic and transforming potential of genotoxic bacteria isolated from CRC precursor lesions using an organoid platform. By leveraging single-cell whole-genome sequencing, we will characterize bacterial mutational signatures and determine their relevance in early tumorigenesis. As Aim 2, we will investigate at which stage and by which mechanisms bacterial adhesion facilitates mutagenesis in FAP. We will focus on the role of bacterial adhesins, particularly novel FimH variants in our bacteria bank, in enabling the colonization of FAP adenomas by genotoxic bacteria. Additionally, we will explore how bacterial cooperation—specifically, the action of bacterial sialidases—modifies host glycoproteins to expose binding sites for mutagenic bacteria. As Aim 3, we will assess the temporal dynamics of bacterial mutagenesis in FAP and explore preventive strategies. Through a prospective cohort study of FAP patients with yearly follow-ups, we will analyze the evolution of microbial composition and mutation accumulation in emerging adenomas of 20 patients over 5 years. Furthermore, we will test the potential of a bacterial adhesin inhibitor to prevent microbe-induced mutations in patient-derived organoids and an in vivo organoid transplantation model. The DETECT group will generate a detailed functional map of microbial mutagenic influences on FAP. We are uniquely positioned to bridge the gap between microbiome profiling and mechanistic insight using our tissue model approaches. Ultimately, our findings will lay the foundation for microbiome-targeted preventive strategies in FAP and young onset CRC.

• DFG Programme: Emmy Noether Independent Junior Research Groups