DKK3 Initially Preserves Acinar Integrity Through MEK-Fos Signaling, but Later Switches to an Oncogenic Role in Pancreatic Cancer.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its intricate biology governed by spatiotemporal dynamics in the expression and function of specific proteins. Here, DKK3 is identified as a dynamic player with a dual role in PDAC. Using the KRAS^G12D-driven mouse model with homozygous (DDKC) and heterozygous (DKC) DKK3 knockout, its stage and compartment-specific functions are investigated. Knockout mice exhibited shorter lifespans with a higher incidence of high-grade, desmoplastic, and metastatic cancers. DKK3-deficient acini exhibited a marked increase in acinar-to-ductal metaplasia, with increased MAPK signaling and induction of the downstream effector Fos. During the progression of mouse and human PDAC, DKK3 expression shifted from epithelial dysplastic cells to c

SUBMITTER: Srinivasan D 

PROVIDER: S-EPMC12806428 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature