title: RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma.
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 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Whittle
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Kamel
authors.initials: K
authors.lastname: Izeradjene
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: P Geetha
authors.initials: PG
authors.lastname: Rani
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Libing
authors.initials: L
authors.lastname: Feng
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Carlson
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: DelGiorno
authors.affiliation: Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.affiliation: Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.affiliation: Departments of Pathology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Chang
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Philamer
authors.initials: P
authors.lastname: Calses
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Shelley M
authors.initials: SM
authors.lastname: Thorsen
authors.affiliation: 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.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism*; D004195:Disease Models, Animal; D016158:Genes, p53; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)