DKK3 initially preserves acinar integrity through MEK-Fos signalling but later switches to an oncogenic role in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its intricate tumor biology complicated by the spatiotemporal dynamics in the expression and function of specific proteins driving such biology. Here, we employ a mouse model with homozygous and heterozygous DKK3 knockout together with pancreas-specific expression of KRASG12D (DDKC,DKC,KC) to investigate the compartment- and time-dependent roles of DKK3. Our findings demonstrate that DKK3 functions to inhibit oncogenesis during the early stages of cancer while paradoxically promoting tumor progression in the later stages. DDKC and DKC mice exhibited significantly shorter lifespans compared to KC mice, with a higher incidence of high-grade, desmoplastic, “cold” and metastatic cancers. Accordingly, DKK3-deficient acinar cells exhibited a marked increase in acinar-to-ductal-metaplasia, accompanied by increased MAPK-signaling with enhanced expression of the immediate-early genes cfos and Jun. Treatment with the MEK-inhibitor trametinib preserved acinar integrity in DKK3-null pancreata. Additionally, FOS-inhibition restricted the migratory capabilities of DDKC cancer cells. Throughout the progression of mouse and human PDAC, DKK3 expression shifted from epithelial cells to the stromal compartment by the endpoint. DKK3-null tumor cells displayed enhanced migratory abilities when exposed to recombinant DKK3. In line, DKK3-expressing cancer-associated fibroblasts (CAFs) emerged as crucial contributors to this tumor aggressiveness. Orthotopic transplantation studies revealed that DKK3 expression within CAFs promotes tumor growth and fibrosis, particularly in aggressive DDKC tumors. Collectively, these findings highlight the complex and context-dependent role of DKK3 in PDAC, suggesting that it may serve as a promising therapeutic target for the management of this challenging malignancy.