RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma

Martin C. Whittle, Kamel Izeradjene, P. Geetha Rani, Libing Feng, Markus A. Carlson, Kathleen E. DelGiorno, Laura Delong Wood, Michael S Goggins, Ralph H Hruban, Amy E. Chang, Philamer Calses, Shelley M. Thorsen, Sunil R. Hingorani

Research output: Contribution to journalArticle

Abstract

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 Run×3 respond to and combine with Dpc4 status to coordinately regulate the balance between cancer cell division and dissemination. Thus, Run×3 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.

Original languageEnglish (US)
Pages (from-to)1345-1360
Number of pages16
JournalCell
Volume161
Issue number6
DOIs
StatePublished - Jun 5 2015

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Whittle, M. C., Izeradjene, K., Geetha Rani, P., Feng, L., Carlson, M. A., DelGiorno, K. E., Wood, L. D., Goggins, M. S., Hruban, R. H., Chang, A. E., Calses, P., Thorsen, S. M., & Hingorani, S. R. (2015). RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell, 161(6), 1345-1360. https://doi.org/10.1016/j.cell.2015.04.048