Cell
Volume 161, Issue 6, 4 June 2015, Pages 1345-1360
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Article
RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma

https://doi.org/10.1016/j.cell.2015.04.048Get rights and content
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Highlights

  • DPC4 dosage regulates RUNX3 levels in a biphasic manner

  • RUNX3 controls the balance between local growth and dissemination in PDA

  • RUNX3 functions as both tumor suppressor and tumor promoter in PDA

  • DPC4 and RUNX3 levels can jointly inform clinical decision making

Summary

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 KrasG12D/+;Trp53R172H/+ 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.

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