Related Experiment Video

Updated: Jan 13, 2026

Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
08:16

Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture

Published on: February 11, 2019

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

Dharini Srinivasan1, Elodie Roger1, Lukas Perkhofer1,2

  • 1Institute for Molecular Oncology and Stem Cell Biology, Ulm University Hospital, 89081, Ulm, Germany.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 28, 2025
PubMed

Insights

Dickkopf-3 (DKK3) has a dual role in pancreatic ductal adenocarcinoma (PDAC). It delays early oncogenesis but promotes later tumor progression, indicating cautious therapeutic targeting.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) involves complex protein dynamics.
  • The role of Dickkopf-3 (DKK3) in PDAC progression is not fully understood.

Purpose of the Study:

  • To investigate the stage and compartment-specific functions of DKK3 in PDAC.
  • To elucidate the mechanisms by which DKK3 influences PDAC development and aggressiveness.

Main Methods:

  • Utilized a KRASG12D-driven mouse model with varying DKK3 knockout levels (homozygous and heterozygous).
  • Analyzed acinar-to-ductal metaplasia, MAPK signaling, and Fos induction.
  • Investigated DKK3 expression shifts during PDAC progression in mouse and human samples.
  • Performed orthotopic transplantations and mechanistic studies involving IL6-JAK-STAT3 signaling.
  • Correlated DKK3 expression with human PDAC gene signatures.

Main Results:

  • DKK3 knockout mice showed reduced lifespan and increased high-grade, desmoplastic, and metastatic PDAC.
  • DKK3 deficiency in acini led to increased metaplasia, MAPK signaling, and Fos induction.
  • DKK3 expression shifted from epithelial cells to cancer-associated fibroblasts (CAFs) during PDAC progression.
  • DKK3-expressing CAFs promoted tumor aggressiveness and fibrosis.
  • DKK3 activated IL6-JAK-STAT3 signaling and pro-migratory programs in PDAC, which were reversed by STAT3 inhibition.
  • DKK3 expression correlated with IL6-JAK-STAT3 signatures in human PDAC.

Conclusions:

  • DKK3 exhibits context-dependent roles in PDAC, delaying early oncogenesis but promoting later-stage tumor progression.
  • DKK3-expressing CAFs are key drivers of PDAC aggressiveness and fibrosis.
  • Therapeutic strategies targeting DKK3 in PDAC require careful consideration due to its paradoxical functions.
Keywords:
DKK3PDACdual roleoncogenetumor suppressor

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