Carmen Mota Reyes, Mara R Goetz, Hana Algül, Alper Dogruoez, Chiara Falcomatà, Matthias M Gaida, Kıvanç Görgülü, Yetiş Gültekin, Ibrahim Halil Gürcinar, Marie C Hasselluhn, Rouzanna Istvanffy, Raghu Kalluri, Valerie S Kalluri, Ashley Kiemen, Pilhan Kim, Sang-Won Lee, Marina Lesina, Peter Yu, Anirban Maitra, Clara M Müller, Sebastian Müller, Dowoon Nam, Kenneth P Olive, Marina Pasca Di Magliano, Roland Rad, Dieter Saur, Matthew G Vander Heiden, Mathias Vormehr, Laura D Wood, Eyüp Yöndem, David Zschäpitz, Didem Karakas, Helmut Friess, Güralp O Ceyhan, European Pancreatic Club (EPC) Pancreatic Cancer Think Tank Group, Ihsan Ekin Demir
Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, as tumors evolve faster than therapies. Resistance is ecological, not merely KRAS driven, involving overlooked players like high-grade pancreatic intraepithelial neoplasias (PanINs), peripancreatic fat, stromal mechanics, myeloid-neural circuits, metabolic rewiring, and systemic host responses. We propose precision interception targeting PanIN/intraductal papillary mucinous neoplasm (IPMN) biology, spatial-functional-proteogenomic classification beyond transcriptomics, the Heracles Protocol (measure, prime, strike, and adapt), and integrated technologies from AI pathology to exosomal delivery and CRISPR-based synergy mapping, together making PDAC more tractable.