Understanding cancer-autonomous versus systemic mechanisms of KRAS-induced necroptotic priming

• Applicant: Professorin Dr. Silvia von Karstedt
• Subject Area: Cell Biology ; Gastroenterology ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553712603

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality. PDAC expresses high levels of caspase 8, a key enzyme that regulates several types of regulated cell death. Using genetically engineered mouse models for PDAC, we demonstrated that oncogenic KRAS-driven neoplastic transformation induces a transcriptional state of necroptotic priming. Therefore, deletion of caspase 8 in PDAC mouse models is sufficient to eliminate the majority of precursor lesions by allowing induction of necroptosis. Mechanistically, expression of the driver oncogene KRAS induces a STING-dependent type I interferon (IFN) response leading to upregulation of necroptosis-associated IFN-stimulated genes (ISGs) including ZBP1 and MLKL, resulting in necroptotic priming. While these data reveal a functional role for increased caspase-8 expression in PDAC and discover necroptotic priming as a new principle, several mechanistic questions arise downstream of oncogenic KRAS expression and type I IFNs, including how oncogenic KRAS activates STING and whether KRAS mutant cells induce necroptotic priming in an auto- and/or paracrine manner in vitro and in vivo. These questions will be addressed as part of this proposal.

• DFG Programme: Research Grants