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

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<sup>G12D</sup>-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 cancer-associated fibroblasts (CAFs). At the endpoint, DKK3-expressing CAFs emerged as crucial contributors to tumor aggressiveness and fibrosis. Orthotopic transplantations confirm a stromal role, particularly in DDKC tumors, while mechanistic studies demonstrate that DKK3 activates IL6-JAK-STAT3 signaling and pro-migratory/mesenchymal programs that are reversed by pharmacologic STAT3 inhibition in DDKC cells. Concordantly, DKK3 expression correlates with IL6-JAK-STAT3 gene signatures in human PDAC datasets. Together, these findings underscore the intricate and context-sensitive role of DKK3, delaying oncogenesis during early stages while paradoxically promoting tumor progression in later stages, suggesting that therapeutic targeting strategies should be approached with caution.

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Publication Details

Journal
Advanced Science
Published
2025-10-28
DOI
https://doi.org/10.1002/advs.202417606
Citations
1
Primary Topic
Cytokine Signaling Pathways and Interactions
Type
article
Field-Weighted Citation Impact
1.05

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article

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

Élodie Roger, Peter Möller, Stefan Liebau, Lukas Perkhofer et al.
1 citations
Advanced Science
Cytokine Signaling Pathways and Interactions
1.05
article

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

Élodie Roger, Peter Möller, Stefan Liebau, Lukas Perkhofer, Chantal Allgöwer, Stephanie E. Weissinger, Nico Fischer, Frank Arnold, Alexander Kleger, Dirk Grimm, Johann Gout, Thomas Seufferlein, Matthias Löhr, Dharini Srinivasan, Nadine Therese Gaisa, Ninel Azoitei, Michael Karl Melzer, Eleni Zimmer, Thomas F.E. Barth, Anna Härle, Julia P. Mosler
article en
1 citations

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<sup>G12D</sup>-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 cancer-associated fibroblasts (CAFs). At the endpoint, DKK3-expressing CAFs emerged as crucial contributors to tumor aggressiveness and fibrosis. Orthotopic transplantations confirm a stromal role, particularly in DDKC tumors, while mechanistic studies demonstrate that DKK3 activates IL6-JAK-STAT3 signaling and pro-migratory/mesenchymal programs that are reversed by pharmacologic STAT3 inhibition in DDKC cells. Concordantly, DKK3 expression correlates with IL6-JAK-STAT3 gene signatures in human PDAC datasets. Together, these findings underscore the intricate and context-sensitive role of DKK3, delaying oncogenesis during early stages while paradoxically promoting tumor progression in later stages, suggesting that therapeutic targeting strategies should be approached with caution.

Advanced ScienceVol. 13(3)
Memorial Sloan Kettering Cancer Center (US), Universität Ulm (DE), Heidelberg University (DE), University Hospital Heidelberg (DE), Karolinska Institutet (SE), Biobyte Solutions (Germany) (DE), Department of Virology (FR), German Center for Infection Research (DE), University Hospital Ulm (DE), Technische Hochschule Ulm (DE), University of Tübingen (DE), Heidelberg University (US)
Deutsche Forschungsgemeinschaft, Österreichischen Akademie der Wissenschaften, Universität Ulm
Openalex Percentile: Top 16%
Cytokine Signaling Pathways and Interactions
1.05
DOIOpen Access PDFOpenAlex
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