Early requirement of rac1 in a mouse model of pancreatic cancer

Irina Heid, Clara Lubesedermartellato, Bence Sipos, Pawel K. Mazur, Marina Lesina, Roland M. Schmid, Jens T. Siveke

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease without effective chemopreventive or therapeutic approaches. Although the role of oncogenic Kras in initiating development of PDAC is well established, downstream targets of aberrant Ras signaling are poorly understood. Acinar-ductal metaplasia (ADM) appears to be an important prerequisite for development of pancreatic intraepithelial neoplasia (PanIN), a common precursor to PDAC. RAS-related C3 botulinum substrate 1 (Rac1), which controls actin reorganization, can be activated by Ras, is up-regulated in several human cancers, and is required for cerulein-induced morphologic changes in acini. We investigated effects of loss of Rac1 in Kras-induced pancreatic carcinogenesis in mice. Methods: Using a Cre/lox approach, we deleted Rac1 from pancreatic progenitor cells in different mouse models of PDAC and in mice with cerulein-induced acute pancreatitis. Acinar epithelial explants of mutant mice were used to investigate the role of Rac1 in vitro. Results: Rac1 expression increased in mouse and human pancreatic tumors, particularly in the stroma. Deletion of Rac1 in KrasG12D-induced PDAC in mice reduced formation of ADM, PanIN, and tumors and significantly prolonged survival. Pancreatic epithelial metaplasia was accompanied by apical-basolateral redistribution of F-actin, along with basal expression of Rac1. Acinar epithelial explants that lacked Rac1 or that were incubated with inhibitors of actin polymerization had a reduced ability to undergo ADM in 3-dimensional cultures. Conclusions: In mice, Rac1 is required for early metaplastic changes and neoplasia-associated actin rearrangements in development of pancreatic cancer. Rac1 might be developed as a diagnostic marker or therapeutic target for PDAC.

Original languageEnglish
Pages (from-to)719-730.e7
JournalGastroenterology
Volume141
Issue number2
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • Cytoskeleton
  • Ductal Cell
  • Genetically Engineered Mice
  • Signaling

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