RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma.

Whittle MC, Izeradjene K, Rani PG, Feng L, Carlson MA, DelGiorno KE, Wood LD, Goggins M, Hruban RH, Chang AE, Calses P, Thorsen SM, Hingorani SR
Cell. 2015 161 (6): 1345-60

PMID: 26004068 · PMCID: PMC4458240 · DOI:10.1016/j.cell.2015.04.048

For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular understanding of these distinct disease manifestations can critically inform patient management. Using genetically engineered mouse models, we show that heterozygous mutation of Dpc4/Smad4 attenuates the metastatic potential of Kras(G12D/+);Trp53(R172H/+) pancreatic ductal adenocarcinomas while increasing their proliferation. Subsequent loss of heterozygosity of Dpc4 restores metastatic competency while further unleashing proliferation, creating a highly lethal combination. Expression levels of Runx3 respond to and combine with Dpc4 status to coordinately regulate the balance between cancer cell division and dissemination. Thus, Runx3 serves as both a tumor suppressor and promoter in slowing proliferation while orchestrating a metastatic program to stimulate cell migration, invasion, and secretion of proteins that favor distant colonization. These findings suggest a model to anticipate likely disease behaviors in patients and tailor treatment strategies accordingly.

Copyright © 2015 Elsevier Inc. All rights reserved.

MeSH Terms (11)

Animals Carcinoma, Pancreatic Ductal Core Binding Factor Alpha 3 Subunit Disease Models, Animal Genes, p53 Humans Mice Neoplasm Metastasis Pancreatic Neoplasms Proto-Oncogene Proteins p21(ras) Smad4 Protein

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