Abstract PR001: Reinforcing acinar identity through NR5A2 enables pancreatic cancer interception by preventing and reversing precancer

Abstract

Pancreatic cancer interception remains an unmet clinical challenge. Available options for high-risk individuals focus on imaging and endoscopic surveillance, yet there are no strategies to actively restrain or eliminate precursor lesions to prevent invasive disease. Recent preclinical studies have shown that direct RAS inhibition can markedly delay progression of precursors into invasive disease, demonstrating that pancreatic cancer interception is feasible. Multiple genome-wide association studies (GWAS) identify the druggable nuclear receptor NR5A2 as a major modifier of pancreatic cancer risk. We and others have established NR5A2 as a master regulator of acinar cell identity required for pancreatic development, homeostasis, and regeneration after injury. We further demonstrate that NR5A2 activity declines with loss of acinar identity, transiently during pancreatitis-induced acinar-to-ductal metaplasia (ADM) and progressively in oncogenic KRAS-driven pancreatic intraepithelial neoplasia (PanIN). Human GWAS pancreatic cancer risk alleles are associated with reduced NR5A2 expression. We therefore hypothesized that reinforcing NR5A2 activity would stabilize acinar lineage identity and intercept pancreatic tumor initiation. Here, we demonstrate that sustained inducible expression of NR5A2 preserves acinar differentiation despite oncogenic KRAS and inflammatory injury, thus profoundly suppressing ADM, PanIN formation, and progression to invasive disease through 40 weeks. Strikingly, NR5A2 activation is not only preventive but also restorative: enforced expression in mice with established PanIN lesions drives re-differentiation of precursor epithelium back toward an acinar state. Together, our results nominate NR5A2 as a compelling target for pancreatic cancer interception. More broadly, these findings suggest that pancreatic precursor lesions retain acinar lineage memory and that acinar differentiation can be restored even after precursor formation. These observations provide genetic proof-of-principle that augmenting NR5A2 activity may represent a durable and complementary strategy for pancreatic cancer interception.