RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma.

Autor:	Whittle MC; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Izeradjene K; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Rani PG; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Feng L; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Carlson MA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., DelGiorno KE; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Wood LD; Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA., Goggins M; Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA., Hruban RH; Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA., Chang AE; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Calses P; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Thorsen SM; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Hingorani SR; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: srh@fhcrc.org.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2015 Jun 04; Vol. 161 (6), pp. 1345-60. Date of Electronic Publication: 2015 May 21.
DOI:	10.1016/j.cell.2015.04.048
Abstrakt:	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.)
Databáze:	MEDLINE
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