Modelling and targeting extrahepatic bile duct cancer

• Applicants: Dr. Lena Rad; Professor Dr. Dieter Saur
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538132723

Biliary tract cancer (BTC) is a devastating disease with a poor prognosis. Even the most advanced systemic therapies only extend life moderately, and patients who undergo tumor resection regularly succumb to recurrence. As a result, BTC has one of the highest death rates of all cancer types, with a 5-year overall survival rate of less than 10%. Intense research in the past three decades has led to important insights into BTC genetics and revealed putative targets for treatment. However, only few reached the clinic to benefit the patient. This is mainly due to a lack of mechanistic knowledge regarding the biological basis of BTC subtypes as well as systematic studies that functionalize cancer genes that drive the disease. So far, such studies have been hampered by the lack of cellular resources and model systems that accurately mimic BTC subtypes. Thus, there is an urgent and unmet need for novel models and functional studies that fill the gap between the genetic landscape and the largely unknown biology of BTC subtypes. To address these gaps, our groups have developed the first genetically engineered mouse models of extrahepatic bile duct cancer (eCCC) and established context-specific roles of distinct oncogenes and tumor suppressors in transformation of the extrahepatic bile duct and the pancreas. We demonstrated that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible towards transformation by activated Pik3caH1047R, but refractory to oncogenic KrasG12D and found that PI3K-signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. Notably, inactivation of p27Kip1 permits KrasG12D-driven eCCC development by bypassing oncogene-induced senescence. Based on our work showing that PI3K signaling and oncogenic KRAS in combination with loss of p27 expression represent essential signaling hubs for eCCC development, we propose a research program that will: (1) Discover and systematically compare cancer drivers of PI3K- and KRAS induced extrahepatic CCC using genome-wide genetic screens in vivo (2) Validate candidate genes and functionally analyze their role in vitro in human organoids and in vivo in mice (3) Generate novel next-generation dual and triple recombinase based genetic models of extrahepatic CCC for spatio-temporal manipulation and the investigation of oncogene dependence of the disease The application of cutting-edge genetic engineering, screening, modeling and profiling technologies will give comprehensive insights into the molecular basis of eCCC pathogenesis and oncogene/subtype specific therapeutic vulnerabilities.

• DFG Programme: Research Grants