Pancreatitis-induced initiation of early onset pancreatic cancer

Abstract Early onset pancreatic cancer (EOPC, <50 years of age), though historically uncommon, is rising in prevalence and frequently presents at advanced stages, underscoring an urgent need for improved early detection strategies and insights into the underlying mechanisms of pancreatic oncogenesis. Chronic pancreatitis (CP), a significant risk factor for pancreatic ductal adenocarcinoma (PDA) and specifically correlated with EOPC, is characterized by profound fibroinflammatory and epigenetic alterations, potentially facilitating KRAS-driven tumor initiation. However, exploration of this process has been constrained by the scarcity of robust human disease models. To address these challenges, we have pioneered the development of patient-derived organoid (PDO) biobanks for normal pancreas (NP), CP, and PDA tissues. Our preliminary studies demonstrate that CP PDOs retain the genetic, transcriptomic, and functional attributes of primary patient tissues, including enhanced fibroinflammatory signaling and ductal dysfunction. In this proposal, we leverage these PDO models to elucidate the mechanistic role of CP in potentiating EOPC initiation. Using immortalized PDOs, we will introduce KRAS mutations to define differential proliferative and oncogenic signaling dynamics between NP and CP backgrounds, complemented by orthotopic transplantation to assess tumorigenic potential in vivo. Furthermore, our comprehensive PDO platform facilitates the identification and validation of novel biomarkers capable of distinguishing EOPC from benign pancreatic conditions like CP. By integrating transcriptomic and proteomic approaches, we prioritize biomarkers with reciprocal expression patterns between PDA and CP. Validated candidates will undergo rigorous evaluation in patient sera, leveraging logistic regression modeling to refine diagnostic accuracy. This integrative approach promises transformative insights into early pancreatic oncogenesis, identifies mechanisms underpinning CP-driven cancer initiation, and accelerates the development of clinically relevant biomarkers for early EOPC detection, thereby enhancing patient prognoses.