2. Academic Validation
  3. FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia

FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia

  • Dev Cell. 2024 Nov 18;59(22):3025-3042.e7. doi: 10.1016/j.devcel.2024.07.021.
Alina L Li 1,  Kensuke Sugiura 1,  Noriyuki Nishiwaki 1,  Kensuke Suzuki 2,  Dorsay Sadeghian 3,  Jun Zhao 3,  Anirban Maitra 3,  David Falvo 4,  Rohit Chandwani 4,  Jason R Pitarresi 5,  Peter A Sims 6,  Anil K Rustgi 7
Affiliations

Affiliations

  • 1 Divison of Digestive and Liver Diseases, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 2 Divison of Digestive and Liver Diseases, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of General Surgery, Chiba University, Chiba 260-0856, Japan.
  • 3 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4 Department of Surgery and of Cell and Developmental Biology, Meyer Cancer Center, Weill-Cornell Medicine, New York, NY 10065, USA.
  • 5 Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan School of Medicine, Worchester, MA 01655, USA.
  • 6 Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 7 Divison of Digestive and Liver Diseases, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
PMID: 39178842 DOI: 10.1016/j.devcel.2024.07.021
Abstract

Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during KrasG12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single-nuclei ATAC-seq and bulk RNA Sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (PanIN) continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.

Keywords

FRA1; G-CSF; KRAS; PanIN; acinar-ductal metaplasia; pancreatic ductal adenocarcinoma; pancreatitis.

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