Related Experiment Video

Updated: Nov 9, 2025

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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Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer

Nawab Azizi1,2, Jelena Toma1,2,3, Mickenzie Martin1,2,4

  • 1Children's Health Research Institute, London, ON, Canada.

Oncogene
|April 17, 2021
PubMed

Insights

Activating transcription factor 3 (ATF3) plays a complex role in pancreatic cancer. Its absence reduced pancreatic ductal adenocarcinoma (PDAC) initiation and progression, but KRAS activation bypassed ATF3

Area of Science:

  • Oncology
  • Cell Biology
  • Gastroenterology

Background:

  • The unfolded protein response (UPR) is implicated in pancreatic pathologies.
  • Activating transcription factor 3 (ATF3) mediates UPR and promotes acinar-to-ductal metaplasia (ADM), an early step in pancreatic ductal adenocarcinoma (PDAC) development.

Purpose of the Study:

  • To investigate the role of ATF3 in the initiation and progression of PDAC.
  • To determine if ATF3 is essential for PDAC development in a mouse model.

Main Methods:

  • Generated Atf3 knockout mice (Atf3-/-) and crossed them with mice expressing oncogenic KRAS (Ptf1acreERT/+KrasG12D/+).
  • Induced pancreatitis using cerulein in Atf3-/- mice with and without KRASG12D.
  • Analyzed morphological and biochemical changes, including ADM, pancreatic intraepithelial neoplasia (PanIN) formation, PDAC development, fibrosis, and immune cell infiltration.

Main Results:

  • Atf3-/- mice exhibited reduced ADM and enhanced pancreatic regeneration after injury.
  • Absence of ATF3 significantly decreased spontaneous PanIN and PDAC formation in KRASG12D mice.
  • Oncogenic KRASG12D largely bypassed the requirement for ATF3 in response to injury, leading to acinar loss and PanIN formation irrespective of ATF3 status.
  • APK mice (Atf3-/- with KRASG12D) showed reduced pancreatic weight, failed to develop PDAC, and had altered fibrosis and immune infiltration compared to controls.

Conclusions:

  • ATF3 plays a multifaceted role in pancreatic cancer, inhibiting early stages but potentially being bypassed by oncogenic KRAS.
  • Targeting ATF3 may offer therapeutic potential, but its interaction with KRAS signaling needs further elucidation for effective PDAC treatment strategies.

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