κB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis

Nat Commun. 2020 Jul 8;11(1):3409. doi: 10.1038/s41467-020-17226-0.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRasG12D-driven PDAC, loss of κB-Ras accelerates tumour development and shortens median survival. κB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. κB-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of κB-Ras proteins and highlight low κB-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / metabolism*
  • Acinar Cells / pathology
  • Aged
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Female
  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism
  • Gene Expression Regulation
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Kaplan-Meier Estimate
  • Male
  • Metaplasia / genetics
  • Metaplasia / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatitis / genetics*
  • Pancreatitis / metabolism
  • Proteins / genetics*
  • Proteins / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • ral GTP-Binding Proteins / genetics
  • ral GTP-Binding Proteins / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • I-kappa B Proteins
  • Proteins
  • SOX9 Transcription Factor
  • GTP Phosphohydrolases
  • ral GTP-Binding Proteins
  • ras Proteins