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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE307602 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely Cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. Here we analyzed if CAFs influence acinar cells and impact PDAC initiation, namely “Acinar to Ductal Metaplasia” (ADM). ADM connection with PDAC pathophysiology is indicated but not yet established. Hence, we hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media (CAF-CM), acinar cell explants, and CAF cocultures, etc., were examined by qRT-PCR, RNA-seq, immunoblotting and confocal microscopy. Data from LC-MS/MS analysis of CAF CM and RNAseq data of acinar cells post-CM exposure were integrated using bioinformatics tools to identify molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and qRT-PCR analysis, we validated the depletion of key signaling axis in cell-line, acinar explant coculture, and mCAFs. Close association of acino-ductal (UEA1, Amylase, Ck19) markers and mCAFs (α-SMA) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased Ck19 and decreased Amylase in wild-type (WT) and KC pancreas. Likewise, acinar-mCAF cocultures revealed induction of ductal transdifferentiation in cell-line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel Laminin5/Integrinα4/Stat3 axis responsible for CAF-mediated acinar to ductal cell transdifferentiation. Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the role of the tumor micro-environment in the inception of pancreatic carcinogenesis.

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

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