Acinar‐Derived Organoids Reveal Stage‐Specific Control of Acinar Plasticity

ABSTRACT Adult pancreatic acinar cells undergo ordered metaplastic conversion during injury and tumor initiation. Whether individual cells retain redifferentiation capacity after metaplastic expansion, and what signals each transition requires, remains unknown. Here, using organoids derived from single acinar cells, we show that expanded acinar‐lineage organoids can reacquire acinar features under stage‐specific culture conditions. We defined conditions that preserve acinar identity ex vivo and showed that epidermal growth factor (EGF)/EGF receptor (EGFR) signaling initiates conversion from this maintained state. The expansion trajectory recapitulates injury‐ and oncogene‐associated acinar‐to‐ductal metaplasia (ADM) programs in vivo. After expansion, the conditions that preserved acinar identity could not restore it; a staged regimen containing transient insulin‐like growth factor 1 receptor (IGF1R) inhibition and dexamethasone promoted redifferentiation. The Kras G12D ;Trp53 R172H ;Pdx1‐Cre ( KPC ) genotype reduced EGFR dependence during initiation but destabilized post‐expansion redifferentiation; Kras ‐pathway inhibition increased endpoint acinar‐marker expression. These findings demonstrate that acinar plasticity is organized by stage‐specific signals, and that the KPC genotype disrupts this control at specific transition points.