Functional mapping of Ras induced immune signalling components in intestinal cancer

• Applicant: Professor Dr. Roland Rad
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550207022

RAS genes are the most frequently mutated oncogenes in human cancer. Using genome-wide in vivo screening and genome profiling of KRAS-driven human and mouse intestinal tumors we observed frequent gene dosage increase of the mutated Kras allele. Allelic imbalance at the Kras locus typically occurred during adenoma-to-carcinoma transition, suggesting a role of oncogenic dosage amplification during early progression. Of note, we found that KrasMUT gene dosage amplification induces strong immune signaling programs in intestinal organoids, including defined chemokine, cytokine and growth factor responses. We propose here to functionally characterize the molecular basis and biological effects of Ras-dosage dependent immune signaling programs (RISP). We will first characterize in detail the quality (mode of allelic imbalance, oncogenic dosage), temporal dynamics (stage-specific effects) and cellular effects (immune signals) of KrasMUT dosage variation using organoid-based models of in vivo disease evolution (aim-1). This will be followed by systematic interrogation of in vivo RISP effects, including immune cell infiltration and activation, extracellular matrix remodeling, invasion or metastasis (aim-2). Using a series of genetic screening approaches, we will then map and mechanistically study the molecular players by which KrasMUT activates distinct immune signaling programs (aim-3). The proposed work will give comprehensive new insights into the evolution and immunobiology of Ras-driven intestinal cancers.

• DFG Programme: Research Grants