FIRE- Fighting pancreatic cancer by origin and niche

• Applicant: Professor Dr. Alexander Kleger
• Subject Area: Gastroenterology ; General and Visceral Surgery ; Hematology, Oncology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555576713

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge in oncology due to its aggressive nature, late diagnosis, and poor survival rates. Current treatment options are limited, with surgery followed by chemotherapy offering the only chance for cure in localized cases, and palliative care being standard for metastatic disease. Despite extensive research, targeted therapies have shown little success in improving outcomes for PDAC patients, highlighting the urgent need for new approaches. The FIRE project aims to tackle these challenges by diving into the intricate biology of PDAC. The disease is characterized by its complex evolution and heterogeneity, driven by diverse genetic mutations and influenced by a dense and immunosuppressive tumor microenvironment (TME). Understanding these dynamics from the earliest stages of tumor formation is paramount for developing effective diagnostic biomarkers and targeted therapies. At the heart of the FIRE project is the hypothesis that early decisions in tumor development profoundly influence the disease's progression and clinical outcomes. To investigate this, the project proposes innovative models using human pluripotent stem cells (hPSCs) to create pancreatic organoids and assembloids. These models will replicate the initiation and progression of PDAC in a controlled laboratory setting, allowing researchers to study how genetic mutations, environmental factors (such as tobacco use or obesity), and interactions with the TME shape tumor development. The methodology involves forward-programming hPSCs into pancreatic cells, mimicking both acinar and ductal origins of PDAC. These cells will be cultured in a novel organ culture system designed to simulate the pancreatic environment, enhancing our understanding of how tumors evolve in response to their surroundings. Additionally, bio-printed stromal components will be incorporated to recreate the complex interactions within the TME, a critical yet often overlooked aspect in traditional research models. By dissecting the early stages of PDAC and exploring its heterogeneity at a molecular and cellular level, the FIRE project aims to uncover novel biomarkers that could enable earlier detection and more precise stratification of patients. Furthermore, by identifying specific vulnerabilities in different subtypes of PDAC, the project seeks to lay the groundwork for personalized therapeutic strategies that could improve patient outcomes. In summary, the FIRE project represents a pioneering effort to bridge the gap in our understanding of PDAC progression using advanced human-centric models. By leveraging cutting-edge technologies and interdisciplinary collaborations, the project aims to revolutionize how we approach the diagnosis and treatment of this challenging cancer, potentially paving the way for significant advancements in precision oncology.

• DFG Programme: Reinhart Koselleck Projects