Project Details
Projekt
Impact of microbial metabolites on translational control in colorectal cancer therapy resistance
Applicants
Professor Dr. Johannes Betge; Dr. Johanna Schott
Subject Area
Gastroenterology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 537604907
Phenotypic plasticity is a major driver of tumour metastasis, recurrence and acquired therapy resistance. While epigenetic and transcriptional mechanisms have been well described, post-transcriptional control is likely to play a large, yet understudied role in this process. PI3K/mTOR signalling, a master regulator of translation and a key integrator of diverse extracellular signals, shows heterogeneous expression in colorectal cancer (CRC) and our cohort of CRC organoids. We hypothesise that specific microbial metabolites affect translation control and thereby plasticity and drug resistance in CRC, mediated by mTOR-dependent and -independent mechanisms. We will analyse the activity and heterogeneity of central regulators of translation in patient-derived organoids and mouse tumours upon treatment with standard-of-care drugs and investigate the effect of microbial metabolites on translation control under therapeutic pressure. Using RNASeq, RiboSeq and proteomics, we will gain a detailed view on mechanisms of drug tolerance/resistance, which integrates the layer of translation efficiency. Finally, we will connect our findings with the analysis of serial biopsies from CRC patients and patient datasets from the GenoMiCC consortium. This may lead to the identification of mechanisms and targets to overcome adaptive treatment resistance.
DFG Programme
Research Units
