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Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation
  1. Guido von Figura1,
  2. John P Morris IV1,
  3. Christopher V E Wright2,
  4. Matthias Hebrok1
  1. 1Department of Medicine, Diabetes Center, University of California-San Francisco, San Francisco, California, USA
  2. 2Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
  1. Correspondence to Dr Matthias Hebrok, Department of Medicine, University of California-San Francisco, Diabetes Center, 513 Parnassus Avenue, HSW 1116, Box 0540, San Francisco, CA 94143-0573, USA; mhebrok{at}diabetes.ucsf.edu

Abstract

Objectives Emerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genome-wide association studies have identified NR5A2, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia.

Design To investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (PdxCrelate; Nr5a2c/c). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion.

Results We show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions.

Conclusions Nr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA.

  • PANCREATIC CANCER
  • PANCREATITIS
  • PANCREATIC DAMAGE

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